Funding for biomedical research is at an all-time low, and as a result, one of the greatest challenges to both the progress of research and the retention of young scientists is obtaining a continuous source of funding.
Funding for biomedical research is at an all-time low, and as a result, one of the greatest challenges to both the progress of research and the retention of young scientists is obtaining a continuous source of funding.
Substance use disorder is a chronic relapsing disorder characterized by a compulsive drive for seeking drug, even if after periods of prolonged abstinence, following presentation of drug-associated contexts or cues. Patients addicted to cocaine, in particular, have high rates of relapse relative to other drugs of abuse. Our lab is particularly interested in the role of prelimbic cortical glutamatergic excitatory projection neurons in cocaine-seeking behavior following abstinence using preclinical animal models of relapse. Specifically, we are interested in how dysfunctional adaptations in prelimbic cortical neurons during early abstinence from chronic cocaine self-administration play a role in subsequent cocaine-seeking behavior (i.e. animal model of relapse), with a specific emphasis on prelimbic cortical projections to the nucleus accumbens core. Previous studies, both preclinical and clinical, have indicated that this specific pathway plays a crucial role in seeking for various drugs of abuse after abstinence. Our previous preclinical studies have indicated that prelimbic cortical glutamatergic transmission is in a quasi hypo-active state during early abstinence, when transient neuroadaptations occur that promote subsequent relapse behavior. Thus, we hypothesized that augmenting glutamatergic neurotransmission within the prelimbic cortex during early abstinence would be sufficient to prevent relapse after abstinence. Moreover, we hypothesized that specifically elevating glutamatergic neurotransmission in neurons in the prelimbic cortex that project specifically to the nucleus accumbens core would suppress cocaine-seeking after abstinence. To address this question, we used a viral-vector approach known as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in order to either; a) activate all prelimbic cortical glutamatergic neurons immediately after self-administration, or b) activate only neurons projecting to the nucleus accumbens core. Preliminary results indicate that activation of all outputs shows a non-significant trend toward suppressing relapse, which is recapitulated by specifically activating prelimbic cortical neurons projecting to the nucleus accumbens core. Overall, our results show that preferentially targeting prelimbic cortical neuron glutamatergic activity, particularly those projecting to the nucleus accumbens core, during the critical early abstinence timepoint following chronic cocaine self-administration may be a therapeutic target for preventing relapse in clinical patients diagnosed with a substance use disorder. The results from these experiments are being presented at the Society for Neuroscience annual meeting in Washington DC in November, 2017.
Yogic Breathing (also known as Pranayama) is a collection of ancient techniques to regulate breathing. Breathing regulation, including slow breathing, deep breathing, breath-holding, and other active breathing practices, are known to improve health in general. Additionally, Yogic Breathing has been shown to help patients with heart diseases, cancer and hypertension. However, the molecular mechanisms for how Yogic Breathing could be beneficial to physical and mental well-being are poorly understood. What is it that makes Yogic Breathing helpful?
We have been studying how Yogic Breathing could help individuals who have or are prone to Alzheimer's disease and other neurodegenerative diseases. When individuals perform Yogic Breathing exercises, they secrete saliva, which contains molecules (like proteins, mRNA, DNA) that can be measured to give us an idea of what is happening within the brain.
In our preliminary study, we had 20 individuals complete either a Yogic Breathing exercise or read quietly for 20 minutes, and we collected samples of their saliva at 5-minute increments. We have already analyzed 20 of the 100 total saliva samples and have seen that the individuals who did the 20-minute Yogic Breathing exercise had molecules (called 'biomarkers') in their saliva after the breathing that weren't there at the start. While these results are exciting and we want to examine this further, we still have 80 samples that we need to analyze before we can do so.
Our primary goal is to measure changes in salivary lipid biomarkers before, during and after a single session of 20-minute Yogic Breathing. We have already collected the saliva samples from 10 'control' subjects, who read quietly for 20 minutes, and 10 'test' subjects, who performed the Yogic Breathing exercise, and we have tested the samples collected at 0- and 20-minutes for the 10 'test' subjects. Our goal with this project is to complete the analysis of the samples taken at the remaining time points (5-, 10- and 15-minutes) for the 'test' group and the samples from all time points from the 'control' group.
Ultimately, this analysis will show us what biomarkers are increased after the Yogic Breathing exercise so we can explore those biomarkers further. Once this analysis is completed, we aim to conduct a larger clinical trial to see if and how Yogic Breathing can help patients with Alzheimer's disease.
Biomarkers are increasingly recognized as a tool for diagnosis and prognosis in various diseases. For example, we can measure the amount of a biomarker that we know is decreased in Alzheimer's disease, aging and other neurodegenerative disorders in an individual's saliva, before and after Yogic Breathing to see whether the breathing exercise has increased its production.
Exploring the molecular mechanisms behind Yogic Breathing techniques will help us understand how Yogic Breathing can be beneficial to patients with, or prone to developing, Alzheimer's disease and other neurodegenerative diseases. Knowing what biomarkers are increased with Yogic Breathing is the first step to gaining a this understanding.
Approximately 20 million adults in the U.S. with diabetes are of low-income and minority populations. This population has an increased vulnerability to diabetes due living in high-stress environments, victimization from violent crimes, family history of domestic violence, personal histories of child physical and/or sexual abuse, and witnessing repetitive community violence. Common health disparities are often overlooked and access to appropriate medical care can be limited. Patient education for diabetes does not address how these previous traumatic experiences affect patients' ability to be compliant with their diabetes treatment plan.
While the effects of mental trauma on health disparities related to Type 2 Diabetes have focused largely on major depression, there is growing evidence that posttraumatic stress disorder (PTSD) is also associated with chronic disease and with poorer health outcomes. A potential contributing factor to the detrimental effects of PTSD and self-management for diabetes is an individual’s difficulty with regulating emotions and stress. Customized modifications of diabetes self-management could help increase patient engagement in both PTSD treatment and compliance with their own diabetes treatment plan. This study will be the first to examine effects of mental trauma as a contributor to the link between trauma exposure and diabetes self-care. The sample population consists of adults that are predominantly from ethnic minority groups (Latino and African American) and all are un-insured, lower socioeconomic families.
In this study, we will be able to look at electronic medical records of patients at two community clinics (Harvest Free Community Clinic and East Cooper Community Outreach (ECCO)) that are well-respected and trusted by this underserved and high needs population.
Individuals will be asked if they would be interested in participating in our survey study, which would involve completion of self report survey to gather information about each patient's emotion regulation, interpersonal violence and abuse history, PTSD symptoms, depression, daily diabetes self management activities, and positive/negative mood. Staff will also gather information from their electronic medical record (EMR) about their HbA1C, medications, other chronic conditions, BMI, and glucose levels. Most importantly, 10 of the participants will be asked to join in a group feedback session with the researchers to share from their perspective what their barriers are to managing their diabetes so that this information can be incorporated into appropriate health interventions.
While some studies may link the connection between PTSD and diabetes with biological changes in the stress regulating systems of the body (e.g., dysregulation of stress reacting hormones like cortisol), this study will determine whether the socio-emotional aspects related to health decision making behaviors may also lead to the development of type 2 diabetes and continue to contribute to poor management of diabetes.
Emotion regulation refers to how each individual handles intense emotions and/or stress (e.g., overeating, becoming more sedentary, impulsive poor choices, forgetfulness). By examining the role of emotion regulation in diabetes management, we can tailor diabetes self management to increase patient engagement in compliance with diabetes treatment plans as well as patient engagement in treatment for PTSD symptoms.
In addition to recruiting enough patients (100) to conduct analyses that are reliable and accurate, we are also relying on the input of patients from this victimized population, who can tell us first-hand what obstacles may be affecting their diabetes self management and can let us know what strategies will be most accepted in their community and how best to share this information with the community in need.
Results from the proposed study will provide pilot data for the NINR R21 application to develop proper modifications to PTSD treatment and/or customized diabetes self-care activities to prevent patient drop-out and/or noncompliance.
Do people with Autism Spectrum Disorder (ASD) perceive faces differently from people who do not have ASD?
Perhaps they perceive faces the same as others, but they are not as interested in faces or are uncomfortable with direct eye contact. There is a wealth of research currently on this topic, some of which has led to the development of training programs to help improve face processing is ASD. However, the generalization of these training programs to real-world everyday functioning has not been strongly demonstrated.
One problem with existing training programs is that they require people with ASD to pay great deal of explicit attention to faces during training. This, of course, makes sense, because the training is intended to improve face skills. But if people with ASD are not interested in faces or are uncomfortable with faces, alternate strategies that minimize extensive exposure to faces may be more beneficial.
The present project will explore alternate ways of training children with ASD to become more proficient at recognizing faces and identifying emotions in faces. The idea that will be explored in this project is to use non-faces to train children with ASD in order to improve their perceptual systems. This, in turn, may benefit their face processing skills.
Participants in this study will visit the lab approximately 3 times for about 1-2 hours per visit. The project will also use neuroimaging (functional magnetic resonance imaging, fMRI) in individuals who elect to participate in order to examine if anything in their brain has changed following training.
One goal of this project is to determine whether training ASD children with non-face objects - like houses, fish or guitars - can improve their visual perceptual skills. This will be measured by how much they improve performance on a matching task performed on a computer during training. This improvement is referred to as “learning.” By comparing training with non-faces to training with faces, this project will determine whether learning is as good with non-faces as with faces, or whether learning with non-faces is even better than with faces.
A second goal is to determine whether training with faces or non-faces generalizes to a task they have not been trained on. This is referred to as “transfer.” One transfer task requires identifying a famous person’s face when presented among other famous or unfamiliar faces. Another transfer task requires identifying specific face emotions, such as “happy,” among faces displaying other emotions. The transfer tasks are intended to reflect real-world everyday face functions.
A third goal is to examine whether there are brain changes associated with transfer. In other words, has the brain reorganized as a result of training and can this be observed when participants perform the transfer tasks?
If this project is successful, it will determine whether training with non-faces in ASD is a viable option for improving face skills. This could ultimately lead to a new behavioral intervention that could help with some of the social processing challenges in ASD.
During this phase of the project, we would like to raise enough funds to test 5 children in the behavioral protocol that would provide useful preliminary data. We hope to raise the initial funding in order to take this study to the next phase and test a total of 10 subjects in the behavioral and brain imaging protocol.
The prevalence of autism spectrum disorders (ASD) is increasing. Recent estimates indicate that 1 in 88 children are now diagnosed. Although the behavioral manifestations of ASD are quite varied across individuals, one of the hallmark symptoms of ASD is difficulty with social communication. The human face is one of the most salient social stimuli in everyday life. We look to faces to identify family members and friends, to try to understand how they are feeling and to aid in verbal and non-verbal communication.
For these reasons, having an intact face processing system is vital to social communication and interaction. However, this capacity may be compromised in ASD, leading to challenges with social relationships. Consequently, research into how face processing can be improved in ASD is an important undertaking both for the individuals affected by ASD and their families and friends.
This project in particular will explore an alternate route to improving perceptual skills that may benefit face processing in ASD. This alternate route may minimize discomfort with or disinterest in faces during the learning process, which may ultimately be a more effective intervention than direct training with faces.
Late-onset Alzheimer’s disease (AD), the most common form of dementia, places a large economic and financial burden on families and society and can be emotionally devastating to loved ones. While we know several things can affect AD, it is an incredibly complex disease, and there are likely other risk factors of AD that we still don’t understand.
Over the past two decades cardiovascular disease (CVD) is being increasingly recognized as an important risk factor of AD. In this project, we are interested in seeing if there are specific changes to genes that are risk factors for CVD and risk factors for Alzheimer’s disease. If we can find genetic risk factors that overlap between CVD and AD, we could target these genes to prevent or delay the onset of Alzheimer’s disease.
One way to identify the genetic risk factors for CVD that are also risk factors in AD is through large-scale genome-wide association studies (GWAS). In GWAS, human genomes – typically ones without a disease and ones with a disease – are compared to see if there are specific changes (or ‘genetic variants’) in the genomes of individuals with a specific disease.
In this project, we plan to take GWAS a step further by using the genomes of patients with CVD to find new genetic risk factors for AD. By using this approach, we intend to identify a subset of genetic variants that are risk factors for dyslipidemia, inflammation (two CVD traits that can be treated and prevented) and AD. As a second step, to understand the role of these risk factors in AD, we will then investigate the relationship between each of these genes and known pathobiological markers of AD.
1) Identify and validate genetic variants associated with AD and CVD traits. We plan to use GWAS to identify genetic variants that are common to traits of CVD (dyslipidemia and inflammation) and AD.
2) Determine the effect that these common genetic variants have on clinical and neuropathological measures of AD. We will determine the relationship between AD/CVD genetic risk variants and the presence of markers known to be elevated in AD.
Late-onset Alzheimer’s disease (AD), the most common form of dementia, effects an estimated 30 million people worldwide, a number that is expected to quadruple in the next 40 years. In the brain (or ‘neuropathologically’), AD is characterized by the presence of amyloid-beta plaques and tau-associated neurofibrillary tangles. Since there are no current disease-modifying therapies and there has been an increasing awareness that symptoms of AD develop over many years, there is a strong need to develop effective strategies to prevent AD. If we could even delay the onset of dementia by a modest 2 years, we could potentially lower the worldwide prevalence of AD by more than 22 million cases over the next 40 years.
Although previous studies have examined the association between AD and CVD traits, no study to date has fully identified the genetic and molecular basis of how dyslipidemia and inflammation influence AD. This project will provide us with a clearer understanding of how CVD and AD are related.
Additionally, this study is the first step in research that is expected to lead to the development of novel strategies for preventing AD. Dyslipidemia and inflammation are effectively managed through current therapeutics; therefore, if we can identify an overlap between the genetic variants causing these CVD traits and AD, we could use drugs targeting dyslipidemia and inflammation to also treat, prevent, or delay AD.
In United States today, disparities in infant mortality rates exist at the racial/ethnic and socio-economic levels. One of the main reasons for this disparity is lack of access to prenatal care due to structural, economic and psychological barriers.
For the past decade, text messages have been used to deliver pregnancy-related education and appointment reminders to low socio-economic women. However, recent research indicates that text messages are not effective for every woman in this group. Some women have limited literacy skills, which impacts their ability to read and interpret written information. Others frequently change their phone numbers, hence continuity of text messages is not guaranteed. Finally, the text messages are somewhat generic in nature, not addressing specific needs or learning styles of these women. Consequently, these populations continue to engage in high risk behaviors resulting in poor pregnancy outcomes.
Mobile applications, when appropriately designed can help address these limitations of text messages but none has been designed for the target population. We designed MomLink specifically for and in consultation with this population. Its graphical interface and linear navigation makes it easy and simple to use by anyone. The app allows a woman to track health indicators, set appointment reminders and communicate with her providers. A web portal has been developed to enable providers to remotely monitor and send personalized multimedia messages to their clients throughout their pregnancies.
We are conducting 12-month study in which 60 pregnant women from low socio-economic communities will use the app. We will compare pregnancy-related knowledge, belief, attitudes and self-empowerment; and birth outcomes data of these women against 60 women who will not use MomLink. Our hope is that MomLink women will have better pregnancy outcomes.
The short-term goal of this research is to improve pregnancy-related knowledge, attitudes and beliefs of women from low socio-economic communities. Another goal is to increase the engagement of the target population in prenatal care. The long-term goal is to reduce the incidences of preterm births, low birthweights and pregnancy complications among the target population. Ultimately, this will result in low infant mortality rates in low socio-economic groups, and a better healthcare for everyone in the community.
This research will scientifically establish the hypothesis that mobile technology is an effective method of influencing knowledge, beliefs, attitudes and behaviors of pregnant women from low socio-economic status (short-term); and of reducing incidences of infant mortality in low socio-economic communities (long-term). This scientific evidence is needed to influence policy decision regarding healthcare and ensuring that every human being, regardless of social status, literacy skills, ethnic backgrounds etc, has access to prenatal care. Finally, the operational details of this intervention may help inform the implementation of other technology-based interventions for other kinds of lower socio-economic populations, e.g. older adults.
Palliative care is customized medical care for those with a chronic illness, type of cancer, or a painful medical condition that decreases their quality of life. Palliative care helps to relieve suffering and the symptoms associated with physical pain. It focuses on improving the quality of life for both patients and their families and is provided by specially trained medical staff to asses the patient's emotional well-being, comfort level, and pain tolerance. .
Eighty percent of patients who need palliative care services live in low to middle resource countries; but only 10% of these patients have access to these services.
Based on evidence from high resource countries, palliative care can improve patient outcomes such as pain control, quality of life, satisfaction with care and the ability to die in one’s own home. At a health system level, palliative care can reduce emergency room visits, hospitalizations and overall healthcare costs. Unfortunately, only limited formative research has been conducted on palliative care in low to middle income resource countries.
The World Health Organization recently recommended that research is needed to adapt and test existing palliative care models for use in low to middle resource countries. To fill the gap in the evidence, we will develop a tailored palliative care intervention that will utilize patient navigators to deliver palliative care in a low resource setting. The study will be conducted in one cancer center located in the outskirts of Kolkata, also known as Calcutta, in India.
We plan to carry out feasibility testing of the palliative care intervention protocol using a single arm trial design. We will need to examine the acceptability of utilizing community-based patient navigators to deliver palliative care services.
We will pilot test the intervention in the 24 South Parganas region served by the SGCCRI over a 3-month period. We will document intervention usefulness, feasibility and acceptability among administrative, clinical and patient/caregiver stakeholders. This process will ensure that our final intervention fits within existing cancer center infrastructure and meets the needs of diverse stakeholders. To conduct this work, we will triangulate information from stakeholder interviews, navigator training evaluations and stakeholder evaluation surveys. We will pilot outcome measures for use in a future study to examine intervention efficacy. Informed written consent will be obtained prior to study participation for all stakeholders who complete interviews/surveys and patients who participate in the intervention.
Through this project, we will develop an evidence-based palliative care intervention that is tailored to the needs and preferences of stakeholders in the region of Kolkata, India. Our initial findings from this study will guide two subsequent research phases:
1) to pilot test the intervention for feasibility, acceptability and initial signs of effect on patients (e.g. symptom control, quality of life) and the health system (e.g. healthcare utilization, cost), and
2) to carry out a large-scale randomized controlled trial of the intervention in the rural regions surrounding Kolkata, India.
The ultimate goal of this research is to develop an evidence-based palliative care navigation intervention that can be broadly disseminated for use across low to middle resource countries.
Adaptive optics imaging allows us to visualize the living human retina with single-cell resolution. This has the potential to transform the way in which retinal diseases are diagnosed and monitored, as well as inform the development of new treatments for patients with eye disease, such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and albinism.
While obtaining adaptive optics images has become routine, there is no standard, validated and robust software tool that can process and analyze these images, which severely limits the clinical appplicability of adaptive optics imaging. Here we propose to overcome this technology gap.
This is an engineering proposal, which are rarely supported by traditional grant mechanisms.
Our goal is to develop a set of open-source objective image analysis tools to understand how light-sensitive rod and cone photoreceptors are arranged on the retina (or the ‘photoreceptor mosaic’). We will leverage our extensive collaborative relationships with retinal imaging labs around the world to ensure the software developed is robust, user-friendly, and practical.
The Advanced Ocular Imaging Program has already succeeded at deploying hardware and software for acquiring image of the living retina, and this project is a natural extension of our mission to improve the clinical use of adaptive optics imaging tools.
We expect to be able to release the first version of this software 6 months after the receipt of funding.
The landscape of retinal disease research is changing rapidly. New treatment approaches are emerging, and it is critical that we develop sensitive, non-invasive biomarkers to correctly diagnose these conditions as well as monitor how well treatments are doing.
We have at our fingertips arguably the world's highest-resolution retinal imaging system, which allows us to image individual cells in the living human retina. However, because software tools with which to extract relevant information from these images are severely lacking, the open-source, validated software that will be developed in this project will benefit all research groups doing similar imaging work.
Osteoarthritis affects 1 in 3 adults over the age of 65 years and 1 in 7 adults over the age of 25 years and leads to long-term disability, significant decreased quality of life and risk of early death. It is critical for doctors to diagnose hip osteoarthritis before the joint is damaged beyond repair, but it is very difficult to assess hip cartilage damage using MRI. Currently, patients are injected with a contrast material that helps doctors better see the hip cartilage with MRI (called an MR arthrogram). However, even with an MR arthrogram, doctors have a hard time seeing the hip cartilage, because the cartilage in the hip joint is relatively thin, and tends to "stick together" making it difficult to separate the cartilage layers covering the two bones of the hip joint.
In this project, we will test if adding a small force ("traction") on the leg to loosen the hip joint during MRI will pull apart the cartilage layers to improve the doctor's ability to diagnose hip arthritis. If successful, this could lead to significant changes in how patients suspected of hip osteoarthritis are diagnosed and treated, potentially affecting millions of lives.
There are two main goals to this project:
1) Assess the improvement in the assessment of hip cartilage damage by adding hip traction to two types of MRI (MRI without contrast and MR arthrogram) using special new techniques (T1rho mapping and T2 mapping) that have been shown to detect really early damage in the cartilage that cannot be seen with routine MRI or x-rays.
2) Assess the feasibility of adding traction MRI to our regular clinical workflow and gather information on its ease-of-use, acceptability, and comfort from the perspective of the hospital staff and patients.
This project will help us at MUSC to assess how we can include this new technique in our clinical practice in a manner that is least disruptive to the hospital workflow and most comfortable for the patients.
At the end of this study, we hope to know if doctors should recommend traction MRI for patients they suspect of having hip osteoarthritis so that they can detect early cartilage damage and recommend a more effective and informed treatment plan. If traction is found to improve the doctor's ability to evaluate hip cartilage damage, and found to be clinically feasible, it has the potential to significantly improve our diagnoses and treatment for people with hip osteoarthritis.
Cigarette smoking-related illness results in an estimated 6,000,000 deaths per year worldwide, yet 20% of adults currently smoke. Among those who attempt to quit, >90% fail.
Shortly after a smoker tries to quit they begin to experience withdrawal symptoms including difficulties with attention and mood. A considerable amount of research suggests that those factors are primary reasons leading a smoker to relapse while trying to quit. Brain imaging research suggests that mood disturbances that ensue during a quit attempt may, in part, be due to disrupted brain function in regions of the brain that are important for decision-making and appraising emotional information (the frontal lobe).
Interestingly, research conducted in our lab and from others shows that different forms of mindfulness practices, such as meditation and Yoga, improve emotional well-being and neural function in the same brain circuits that we find to be disrupted in cigarette smokers. Therefore, mindfulness training through Yoga may provide a safe, affordable and highly accessible approach for helping individuals to manage mood-related problems and improve decision-making during a smokers attempt to quit smoking. Our goal is to help improve a smokers odds of succeeding during a quit attempt.
We recently developed an eight-week manualized Yoga training protocol aimed to help smokers quit smoking. Our Yoga protocol is designed to improve both emotional and physical well-being and teach participants how to use the Yoga skills to improve attention and mood.
Over the course of eight weeks, participants will be asked to attend weekly yoga training sessions for 1.5 hrs/week and fill out a number of questionnaires related to their physical and emotional health and their smoking behavior. In addition, we will measure changes in smoking behavior and mood and collect brain imaging data (fMRI) while participants are asked to make decisions about emotional images.
This work represents an early-phase proof of concept for using this Yoga intervention to help cigarette smokers quit smoking. We anticipate this research will take 12 months to complete.
The primary goals of this project are to examine the effects of this new Yoga protocol on:
1) reducing smoking behavior
2) improving emotional health
3) changes in brain function and structure.
Smokers will be prompted to quit smoking in the latter stages of the protocol. The effects of treatment on behavior, mood and brain function will be examined as predictors of smoking cessation outcomes.
Findings from this project will be used toseek additional funding from the National Institutes of Health to conduct a larger scale study.
In the U.S. alone, cigarette smoking is the number one preventable cause of premature death and costs ~$200 billion per year in illness and lost productivity. In spite of all of our efforts to help smokers quit smoking, the percentage of daily smokers in the US has plateaued at ~20% over the past decade. Therefore, cigarette addiction is not only harmful to the individual smoker, but takes an immense toll on society.
While a large percentage of men will develop prostate cancer (age trends range from ~50% in their 50s up to ~90% in their 90s), only a small percentage will die from it. As a result, the biggest problem in prostate cancer is deciding which patients to observe or treat (immediately or after surgery or radiation). As the past standard of overtreatment has yielded to ”active surveillance”, without improved decision-making tools, more untreated men are likely to develop life-threatening metastastis, or spread of the cancer to other parts of the body.
Our multidisciplinary team has developed and published a “Thawed Live” method that allows tissues and tumors to be frozen such that when thawed, they behave as they were when they were freshly isolated. Furthermore, we can keep these thawed tissues alive and intact so we can study them for over a week. We have also previously shown that if we put tumor cells into thawed living lung tissue outside of the body (or ‘ex vivo’), they can grow and show traits that metastatic tumor cells have when they grow in the human body (or ‘in vivo’).
Here, we propose to take patient prostate tumor cells, infuse them into live lung tissues and monitor their growth and metastatic traits ex vivo using cutting edge molecular imaging and genomics on tissues. The goal of this project is proof-of-principle: do traits of primary prostate cancer cells in our “metastatic” organ model serve as a useful tool to distinguish life threatening, treatment-worthy cancers from those that are not? If we can see correlations between molecular signatures in tumors and traits in thawed live lung tissue, we may be able to identify features that may be predictive indicators of tumors with metastatic potential for men undergoing prostate cancer biopsies.
The goal of this project is to develop new tools to help clinicians decide which prostate cancer patients are more likely to develop life-threatening metastatic disease and require particular treatment regimens. Our novel “Thawed Live” and ex vivo co-culture methods used are anticipated to predict the fate of prostate cancers, and in so doing, can be used with cutting edge molecular imaging and genomics to tease out signatures in initial tumor biopsies that correlate with metastatic potential.
Milestones for achieving this goal are:
1) Coordinate Pathology & Urology Departments to utilize patient history and biopsy features, such as tumor Grade (“Gleason score”) to select and isolate primary tumors and lung metastases from 3-5 patients.
2) Freeze multiple portions of these tumors by our “Thawed Live” method for repeated use.
3) Thaw and Fluorescent tag tumor cells and infuse them into thawed live lung tissue.
4) Perform “ex vivo” co-culture, monitor tumor cell growth rates and molecular features of metastasis
5) Characterize the most and least aggressive tumors.
6) Coordinate with Genomics and Bioinformatics cores to characterize fresh thawed cells from the initial tumors.
Through these milestones, we will tease out molecular signatures in initial biopsies that would predict which tumors are likely to be aggressive. Reaching beyond this project, our overall goal is to utilize “Thawed Live” human bone & lung tissues as decision-making tools to assess metastatic potential and preemptively create accurate metastatic tumor cell targets for effective drug therapies in breast, lung, kidney and prostate cancers.
The decision to treat cancers and identifying the optimal treatment are two of the toughest issues facing Oncologists. The rapid emergence of multiple candidate drugs that potentially could be used to treat metastatic tumors underscores the need for better decision-making tools. These decisions would be greatly facilitated if we could culture a patient’s tumor under conditions that accurately simulate how the tumor’s in vivo features, especially its metastatic potential and responsiveness to candidate agents. To this end, we are developing models where “Thawed Live” human tissues (that act as if freshly isolated) are infused with tumor cells and used as 'incubators' for growth. These models will facilitate detection of tumors that demonstrate the ability to metastasize and create accurate metastatic tumor cell targets for effective drug therapies.
In this proposal, we address the single most important problem in prostate cancer today: whether to observe or treat men with cancer. We are addressing this problem with a highly innovative and unparalleled approach that will 1) revolutionize the way tumors and tissues are banked/preserved and 2) provide an improved, patient-pertinent alternative to animal model studies and rationale for improved clinical trials.
Genetically engineered animal models have been the cornerstone for identifying key regulators in cancer. Among these elegant animal models, advanced prostate cancers show extensive metastasis to the lungs. Unfortunately, these elegant animal models cannot account for variability in genetics and exposure history of the patient that can dramatically impact key regulator interactions and consequently responsiveness to therapies and metastatic potential.
The aim of this pilot project is to examine brain iron levels in healthy adolescents and young adults who illicitly use psychostimulant medications (i.e., performance enhancing, recreational). Psychostimulant medications, such as Ritalin or Adderall, are the first line treatment for attention-deficit/hyperactivity disorder (ADHD) and are successful in reducing inattentive and hyperactivity/impulsivity symptoms for the majority of ADHD cases. However, reported side effects for nonresponsive cases have been as severe as addiction or psychosis (mental instability). These adverse side effects underscore the possible risks associated with inappropriately taking psychostimulants, either from misdiagnosis or without a prescription.
Within the past decade, the 42% increase in the rate of ADHD diagnosis has given more youth access to psychostimulant medications. This over availability of psychostimulants has inadvertently resulted in a public health problem: increased rates of misuse, abuse and divergence (selling/sharing) of psychostimulant medications in adolescents and young adults. Despite this growing trend, the effects of illicitly using psychostimulant medications on the healthy developing brain remain unknown.
What is known is that psychostimulants increase the levels of a neurotransmitter called dopamine. In the case of ADHD, where dopamine deficiency is suspected, taking psychostimulant medication increases reduced dopamine levels back to normal. But what happens to the brain of an individual who already has normal dopamine levels but takes psychostimulant medications, especially more than once? Evidence suggests that regulation of dopamine levels (or ‘homeostasis’) is integral to understanding psychostimulant effects on the brain; however, we currently have no way of monitoring brain dopamine levels without the use of potentially harmful radiation.
The goal of this pilot project is to non-invasively examine brain changes in healthy adolescents and young adults who illicitly use psychostimulant medications. Although psychostimulants are known to alter dopamine levels in the brain, all current methods for quantifying dopamine require the use of radiation. Alternatively, as brain iron is required for dopamine metabolism and can be quantified non-invasively with MRI, my approach is to measure brain iron as an indirect biomarker of dopamine changes. Specifically, I will use the raised funds to collect MRI data from healthy adolescent and young adult males who illicitly use psychostimulant medication and then compare these results to age-matched male controls using control data previously acquired from another study.
Increased rates of misuse, abuse and divergence of psychostimulant medications in adolescents and young adults have become a major public health problem. Despite the fact that psychostimulant medications have a high potential for abuse, the ubiquitous use of these medications have resulted in a false societal belief that these medications are harmless. Indeed, reports of healthy high school and college students taking psychostimulant medications to study for exams and/or improve grades are alarmingly common. Despite this growing trend, the effect of illicitly using psychostimulant medications on the healthy developing brain remains unknown.
Thus, the importance of this pilot study is that it will be the first to examine effects of illicitly using psychostimulant medications on the healthy developing brain. If brain iron changes are found, these findings will serve as a public health reminder of the biological risks associated with inappropriately using psychostimulant medications. Moreover, the data collected from this study will establish that measuring brain iron is a non-invasive and clinically-feasible method to monitor brain dopamine levels; such a biomarker could have an important impact on understanding the therapeutic limitations of psychostimulant medications.
My career goal is to identify brain biomakers that can distingush which healthy individuals are at higher risk of developing psychostimulant addiction and compare them to biomarkers in ADHD patients who develop this addiction versus those who do not.
Diseases such as cancer, heart disease, and diabetes tend to ‘run in the family’. So a detailed family health history can help identify health risks. Unfortunetly, we often don't do a good enough job keeping track of our family health history.
So we developed an online social network for family health called ItRunsInMyFamily.com that helps collect and share family health information with relatives.
The website also uses artificial intelligence to help collect essential information and provide personalized care recommendations.
We have identified nearly 500 recommendations that could implemented within ItRunsInMyFamily to help identify families at increased risk and refer them to the appropriate care.
ItRunsInMyFamily.com, what runs in yours?
Check out our research!
The goal of this project is to implement cancer guidelines and recommendations within ItRunsInMyFamily, so families who are at increased risk can receive appropriate care.
Most children with Duchenne or Becker muscular dystrophy develop heart disease by their 18th birthday. These children have the “wrong” genetic message or mutation in their dystrophin gene and as a result, the muscles in their legs, arms and heart grow very weak. Unfortunately, 20-50% of these patients die from heart complications.
Even with standard imaging tests, it is difficult to diagnose heart involvement in these children. As a result, a big problem in muscular dystrophy is recognizing heart damage at an early stage when treatments can be life-saving. Our goal is to discover a novel protein or biomarker that can be developed into a clinical test in order to detect subtle signs of heart disease before it becomes too late.
In our research laboratory, we are able create heart and skeletal muscle cells from a small sample of urine. In this manner, we can use these heart and skeletal muscles cells to study differences between skeletal and heart muscles without any risk to the patients. We would like to use these special cells to find proteins that are specific to heart muscle damage that could be a candidate for a specific indicator (or "biomarker") of heart disease in muscular dystrophy.
The goal of this project is to discover novel protein biomarkers that could be further developed into a test that would help clinicians diagnose heart damage in children with muscular dystrophy. These tests would improve the survival and quality of life for these children.
Findings from this project will be used to seek additional funding from the National Institutes of Health or the Department of Defense in order to increase the scope of the project.
Heart failure is a common and serious feature of Duchenne and Becker muscular dystrophy. Over time, the diminished or aberrant dystrophin protein damages normal operation of this all-important muscle. Once the heart becomes damaged, patients are prescribed medications to protect against further heart damage. Often, the heart damage is not detected until it is quite severe and medications are no longer useful. This happens because of limitations in the way doctors currently assess heart damage -- by ordering imaging tests like echocardiography or cardiac MRI. Even though these imaging tests are the best way to assess heart damage, they are far from being a perfect test.
It would be helpful to have a biomarker test that we can use to detect subtle heart damage in the blood or urine before the imaging tests become abnormal. However, this has been difficult to develop because skeletal and heart muscle cells contain a lot of the same proteins.
To circumvent this difficulty, we have developed a novel tool that we can use to study differences in proteins between skeletal and heart muscles. By using master (or "pluripotent") cells from patients with muscular dystrophy and a groundbreaking method called "cellular reprogramming", we can coax the pluripotent cells to form either beating heart muscle cells or skeletal muscle cells. This remarkable new technology allows us to study how a genetic mutation affects the heart or skeletal muscle cells of a specific patient. We then have the ability to test the difference between skeletal muscles and heart muscle cells without carrying any risk to the patient.
Overall, this project will allow for the discovery of new protein biomarkers that might detect disease of the heart muscle in muscular dystrophy patients. It will also lead to further understanding on how mutations in the dystrophin gene affect skeletal and heart muscle cells differently.
The Fourth Annual Symposium for Advocates of Women in Science and Medicine will be held Saturday, March 25th, 2017 at the University of Virginia. There will also be a multi-professional networking dinner following the symposium. This will be a day focused on career advancement and advocacy for women in science and medicine!
This year's symposium will feature Dr. Vivian Pinn as keynote speaker, who will share her pathway through medical training as well as her work on advocating for women in science and medicine. We will also have Kimberley Barker speak on managing online presence as a medical and/or research professional. In addition, the day will include a poster session, networking workshops, and focused panels on topics including career development, work-life balance, and inter-professional collaboration.
We have a group medical and graduate students who will drive up from Charleston, SC to Charlottesville, VA to attend the Fourth Annual Symposium for Advocates of Women in Science and Medicine.
We hope to raise some money to help fund our lodging for two nights at the conference.
The goal of this meeting is to educate members about inequalities women in research and medicine face and generating educational and networking experiences for students to help overcome these obstacles. This symposium importantly brings together advocates (male and/or female) for women in science and medicine (from across many disciplines) to facilitate discussion of challenges, goals, tools, and opportunities women face in science and medicine. By including participants from across medical, graduate, and nursing education we can have in depth conversations and facilitate connections across these disciplines (adapted from http://uvaaffirm.wixsite.com/southeastsymposium).
This project will examine the role of cholesterol-lowering medications, i.e. statin therapies on the brain. The goal of statin therapy is to prevent the occurrence of heart attacks and stroke by lowering one’s cholesterol, thereby regulating plaque build-up and vascular events. However, cholesterol is also a vital building block for myelin, which provides support for the brain and its connections. Since cholesterol is a vital component of myelin, and myelin is critical for cognitive function, changes in cholesterol levels by statins may also impact cognition.
In 2012 the FDA issued a warning that changes in memory and thinking were a known side effect of statins. As most research completed to date has been aimed at identifying risk reduction for vascular events, previous studies have not examined the direct impact of statins on brain function. The mechanism for this relationship therefore remains unclear. Furthermore, it remains controversial whether women derive the same risk-reducing benefits as men and they often experience a greater number of side effects. Despite this, women have historically not been as involved in clinical trials. We seek to address these gaps in the literature.
This study uses quantitative high field (3 Tesla) Magnetic Resonance Imaging (MRI) and cognitive testing to evaluate the brain’s microstructure and function. We plan to perform a longitudinal study, evaluating patients’ brains before initiating treatment and after 12 weeks of statin use in 20 women ages 45-85. The same procedures will be performed on 10 age-matched controls who are not prescribed or taking statins.
At the completion of this project, we aim to successfully quantify the effects of 12 weeks of statin therapy on the microstructure and function of the brain. In doing so, we hope to elucidate the possible effects of statin use on brain function, and offer a potential mechanism for observations of even subtle cognitive dysfunction in otherwise neurologically healthy adults.
In response to the increasing number of heart-related deaths and rise in heart disease in the U.S. statin drugs were first introduced in 1987 to reduce cholesterol levels in the body. According to the National Center for Health Statistics, statin use increased from 20 to 28% over the period of 2003-2012, reflecting a tremendous expansion in how these drugs are now prescribed. Importantly, in 2012 the FDA issued new warning label changes that identify memory loss and confusion as significant side effects, though this has seemingly not impacted prescription rates. By quantifying the microstructural and cognitive changes that accompany statin use, this study aims to generate objective evidence on the effects of stain use on the brain. Critically, this may catalyze future investigations on the specific indications and conditions required to justify statin use and support the identification of individuals particularly vulnerable to its effects.
My study is the first to use a novel brain imaging technique that allows us to examine the structural details of the brains of children with epilepsy. We can then connect these structural details to symptoms of depression found in these children. In more specific detail, my study links neuropsychological measurements with structural brain imaging to evaluate whether depressive symptom are associated with specific volume changes in the brains of children with epilepsy. Twenty-five children with epilepsy were evaluated for depressive symptoms and were imaged with magnetic resonance imaging (MRI). The study found that in specific brain regions there was an increase in gray matter volume that was associated with a higher overall depressive symptom severity. Further, specific groups of depressive symptoms are associated with gray matter changes in the same brain regions. These findings provide evidence for progressive reorganization of brain networks, supporting the presence of diverse patterns or clusters of depressive symptoms in children with epilepsy. Knowledge that specific brain regions are involved in depressive symptoms may help tailor and improve treatments and subsequent outcomes over the course of epilepsy and quality of life.
My aim is to improve our understanding of the neurobiological changes that occur in children with epilepsy and the associated cognitive and behavioral health comorbidities, and to identify biomarkers that may assist in predicting the effect of (non-)surgical treatments. My research combines clinical and neuroimaging techniques to examine behavioral health functioning in children and adolescents with epilepsy. Understanding how and when comorbidities, such as depression, anxiety, learning disorders and ADHD occur with epilepsy could lead to improvements in the way we identify and treat both epilepsy and its comorbidities.
My research was accepted for presentation as a poster at the largest, most well respected, and innovative scientific meeting in the field of epilepsy - the American Epilepsy Society (AES). Why is it important for me to present this data? Perhaps, one of the most important benefits is the ability to advocate for children with epilepsy by presenting my findings to other epilepsy researchers and clinicians, but also to increase public awareness of this innovative research in my field. Because my research provides a link between interdisciplinary fields, it is imperative that I interact with other excellent researchers from different fields and exchange ideas, as well as receive productive feedback about my work. Attending the AES meeting in Houston in December and presenting my findings will give me the opportunity to discuss my research and learn valuable information from people working with similar techniques and populations.
Epilepsy is one of the most common neurological disorders during childhood and adolescence. More than 450,000 children and adolescents in the United States currently live with epilepsy. Odds of depression in this population are threefold compared to healthy children, but also higher than in kids with other neurological disorders (e.g., migraine), suggesting that neuropathophysiological and/or psychosocial factors (e.g., uncertainty associated with unpredictability of seizures, social isolation, independence with self-management, and driving restrictions), specific to epilepsy may provide more “insult” for children with epilepsy.
Given the complexities of depression in children, it is important to examine specific symptoms of depression in children with epilepsy. To date, no study has investigated structural brain changes in relation to specific clusters of depressive symptoms. The current study is the first to use a specific brain imaging technique called voxel-based morphometry (VBM), which allows the examination of differences in brain anatomy, to relate structural brain changes in children with epilepsy to different clusters of depressive symptoms. The proposed project is significant for the following reason: it will potentially identify a biomarker for epilepsy comorbidities and inform further needed research regarding brain networks, epilepsy comorbidities, and neuroimaging in children with epilepsy. Understanding how different depressive clusters relate to specific brain regions could inform treatment methods and decrease the severity of epilepsy comorbidities.
I will be conducting research alongside Dr. Ablonczy to scan for physical changes in retinas in response to glycation products and B-amyloid substances. Diabetic macular edema (DME) is the accumulation of fluid within the extracellular spaces of the neuroretina. DME is a principal cause of vision loss in diabates, thereby carrying enormous social and economic burdens. Early studies focused on leaky retinal blood vessels as the principal source of the edematous fluid. However, more recent data suggest that impaired fluid transport from the neuroretina by the retinal pigment epithelium (RPE) plays a critical role in the accumulation of fluid. Our long-term objective is to understand how endogenous and environmental factors impact the ability of the RPE to maintain extracellular fluid balance in the retina and prevent edema.
The pattern recognizing receptor for advanced glycation end-products (RAGE) belongs to the immunoglobulin super-family. The activation of RAGE has been shown to contribute to a variety of conditions: Alzheimer disease, cardiovascular and microvascular disorders, tumor angiogenesis, and atherosclerosis. One of the high-affinity ligands of RAGE is amyloid-42. During aging or metabolic stress, amyloid-42 is increased in ocular humors leading to the activation of RAGE in the RPE. New data from our laboratory provides evidence that RPE barrier function is compromised by amyloid-42 and that ihibition of histone acetylation reverses this response. The goal of this project is to understand the role of amyloid-42 in the breakdown of RPE fluid transport, so that we can design medications to treat diabetic macular edema.
Current treatments of DME are risky and invasive. Therefore, new approaches are required for efficient and safe pharmacological interventions to stop or reverse the condition.
Aphasia, or language impairment permanently affects one third of patients surviving a stroke in the left hemisphere. Speech therapy can be effective to improve communication for some patients, but unfortunately, not everyone responds well to treatment and to date little is known about what drives rehabilitation success. A popular hypothesis suggests that recovery-related neuroplasticity is associated with the strengthening or the re-establishment of structural connections between key related brain regions. In this study, we aimed to test this hypothesis by assessing the relationship between therapy-related improvements in naming errors and microstructural white matter fiber properties, using innovative assessments of mean kurtosis (MK), which is a novel and sensitive metric of microstructural complexity, measured longitudinally along white matter pathways associated with the dorsal and ventral stream for language processing. Our results suggest that with therapy the center of the ILF becomes increasingly complex if less semantic errors are made. Contrarily, the SLF displays a more complex microstructure if more phonetic errors are made, possibly a reflection of a therapy related increase in speech production. These results likely fit the dual stream model for language, as changes in the dorsal pathway (SLF) correlated with changes in articulation and changes in semantics reflected as microstructural changes in the ventral stream (ILF).
I would love to present this abstract at the annual meeting of the society for the neurobiology of language. Upon finishing my first year as a PhD student, I am most eager to learn about the latest discoveries in the field and how I can integrate these in my own work. I still have a lot to learn about neuroscience, especially how it applies to language. Hence, I believe that attending SNL will be very fruitful for my professional advancement. During the last semester, I attended an 8 semester hour course on the fundamentals of neuroscience, providing me with the basis to understand the work presented at the conference. I am excited to start studying the neurobiology of language, and I believe that attending this meeting will significantly impact my work. The opportunity to share my work and meet with leaders in the field will be an excellent way to establish myself.
Cerebrovascular accidents are the leading cause of disability in the United States. Aphasia, a deficiency in language processing, is common consequence of a dominant hemisphere stroke and often associated with significantly reduced quality of life. The symptoms of aphasia can vary across different
subjects, including different degrees of difficulties in producing and understanding language. Treating patients with aphasia is complex and consists in multiple and intensive sessions of speech therapy. Unfortunately, not every patient responds well to therapy and to date little is known about what guides post-ischemic tissue remodeling, neuroplasticity, stroke and aphasia recovery. If we were able to better understand the mechanisms associated with recovery from cerebrovascular injury, this information could be used to improve patient counseling, guide treatments and improve therapy approaches.
A popular hypothesis suggests that recovery-related neuroplasticity is associated with the strengthening or the re-establishment of structural connections between key related brain regions. We propose to use neuroimaging to assess the neuroplasticity of stroke recovery by studying structural brain changes induced by speech therapy, as well as by evaluating how spontaneous recovery and speech therapy are associated with the reorganization of neuronal networks. The significance of this project is twofold. First, the investigation of structural changes could provide new insights related to the neurobiological mechanisms associated with stroke recovery. Second, by investigating personalized patterns of tissue integrity, this research may lead to the development of markers for recovery potential after a cerebrovascular incident.
The Gotbeters, a local Charleston family, adopted their daughter, Molly, from China when she was three years old. Unlike most toddlers, Molly has spina bifida, a birth defect where, early in embryonic development, a portion of the neural tube doesn’t close properly near the base of the spine. Since adopting Molly, the family has been working with doctors to get her treatment, which has required many doctor’s appointments.
As anyone who visits the doctor knows, one of the most common ways to quickly test for a myriad of conditions is through a urine sample, and with Molly’s condition, this was something that had to be done often.. Have you ever tried to get a urine sample from a wriggling, impatient three-year-old? It’s a feat. If getting a ‘clean’ sample isn’t possible, the next step is to use a catheter, which is even more traumatic – for anyone at any age.
Spurred on by an advertisement by the MUSC Foundation for Research Development (FRD), the university’s tech transfer office, the family submitted an idea they had come up with for a urine collection device that would make their lives – and the lives of other parents trying to take urine samples from children – easier. Not only is this device helpful for obtaining hygienic samples from children, it is useful for anyone who has a difficult time voiding while holding a cup, such as the elderly and hospital patients.
The device is simple: it is a disposable, urine collection system that has a plastic liner that release-ably mounts to a toilet bowl, rim or seat, and contains a basin in the center for the urine. The basin has a stopped port that can drain the urine into any specimen container. It fits on a variety of toilet sizes, ranging from a toddler potty to a full-sized toilet seat. Because it is hands-free, it allows for a more hygienic collection and makes the process simpler, particularly when holding a cup is challenging or impossible.
Thankfully Molly had surgery last year to fix the majority of the effects, and she is a happy four-year-old, but there is a very large population that are still in need of an easy and hygienic way to collect a urine sample for their health.
A provisional patent application has been filed for this device, and we currently need to develop a working prototype. These funds will be used to support building the prototype, which we will use as a working model to help license the technology, and ultimately have this product go to market.
This device works for any and all applications that may require urine collection and for all populations.
Urinalysis is performed as a part of most routine medical examinations, including pregnancy checkups and drug screening, and is necessary for diagnosing and monitoring conditions like urinary tract infections, kidney and bladder disease, and back or abdominal pain. The ‘clean catch’ method is typically used to collect urine samples to avoid contamination, but this is difficult for most to complete hygienically. Additionally, if a patient needs assistance, the process can be unsanitary and embarrassing, and if it is too difficult, the doctor may end up having to use a catheter, which is uncomfortable and even painful.
While there are other urine collection systems, all current devices have limitations such as not being disposable or not being configured to fit specific specimen containers. Additionally, they don’t fit a range a toilet sizes.