Professor, Department of Physiology, College of Medicine

UK CCTS - Barnstable Brown Diabetes Center Collaborative Award

Feeding Behavior is an ANS-targeted Strategy to Mitigate Arrhythmias in Diabetic Mice

Associate Professor, Department of Physiology, Spinal Cord & Brain Injury Research Center, College of Medicine

UK CCTS - Spinal Cord and Brain Injury Research Center Collaborative Award

The role of immunometabolism in traumatic brain injury

Assistant Professor, Department of Neuroscience, College of Medicine

UK CCTS - Spinal Cord and Brain Injury Research Center Collaborative Award

Metabolic regulation of spinal cord repair by astrocytes

Assistant Professor, Department of Health, Behavior, and Society, College of Public Health

UK CCTS - Markey Cancer Center Collaborative Award

Cultural Adaptations to a Custom-Recordable Audiovisual Tool to Reduce Colorectal Cancer Screening Disparities among Black Kentuckians

Assistant Professor, Department of Pharmacology and Nutritional Sciences and Sanders-Brown Center on Aging, College of Medicine

UK CCTS - Sanders Brown Center on Aging Collaborative Award

Contribution of activated astrocyte-derived fibronectin to vascular dysfunction in a mouse model of Alzheimer’s pathology

Professor, Department of Radiation Medicine, College of Medicine

UK CCTS - Markey Cancer Center Collaborative Award

Inhibition of Drug-resistant Lung Tumor Growth Using p53- and Src-activating Drug Combinations

Associate Professor, Department of Pharmacology and Nutritional Science, College of Medicine

UK CCTS - Sanders Brown Center on Aging Collaborative Award

Sex‐selective increases in white matter neurovascular unit ceruloplasmin in Alzheimer’s disease

Associate Professor of Pharmacology and Nutritional Sciences, College of Medicine
Associate Director for Translational Research in Diabetes, Barnstable Brown Diabetes Center

UK CCTS-Barnstable Brown Diabetes and Obesity Center Pilot Award

Does aging-associated autophagy predict or promote inflammation and type 2 diabetes

Healthy life-span, or healthspan, has improved over the decades owing to better health care. However, longer lifespan is often accompanied with age-associated metabolic disorders such as type 2 diabetes (T2D), which severely compromise healthspan. Cellular mechanisms that may support aging-associated metabolic decline include mitochondrial dysfunction, autophagy defects, and age-associated inflammation, or inflammaging. Inflammaging is a non-resolving inflammation due to factors such as low intensity immune cell stimulation and excessive long-term responses in target tissues. The proposal work is based on evidence of coincident shifts in autophagy and pro-inflammatory cytokine profiles of human immune cells from aged or metabolically compromised individuals. We propose to study the effect of autophagy-arbitrated changes in cytokine profiles in younger compared to older people with and without T2D to test the central hypothesis: age-associated decline in immune cell autophagy increases inflammation and predisposes T2D.  The objective of our work is to compare inflammatory profiles using our published bioinformatic approaches and cells from older T2D, older non-T2D (ND), young T2D and young ND subjects, and to begin to define contributions of T cell autophagy to the putative T2D-promoting cytokine profiles in aging

Assistant Professor, Department of Neuroscience, College of Medicine

UK CCTS - Spinal Cord and Brain Injury Research Center Pilot Award

Regulating dystrophic functions of aged astrocytes following traumatic brain injury

The broad and long-term goals stemming from this pilot proposal are to form a significant knowledge-base surrounding the role of aged astrocytes in the propagation of neurodegenerative sequelae after TBI. TBI in the aged population represents a significant unmet healthcare challenge, as advanced aging is a strong risk factor for acquiring a TBI, and subsequently developing neurodegenerative disease such as Alzheimer’s disease. Despite the fact that aged individuals are increasingly more likely to develop Alzheimer’s disease following a TBI, in tandem with disparately worse comorbidities, the research data concerning this at-risk population is scarce. In Aim 1, this pilot proposal will examine the heterogeneity of astrocytes’ acute response to injury in the context of young (3m) versus aged (22m) mice, as well as how VIVIT, a novel regulatory peptide, may interfere with this response to injury. In Aim 2, we will determine if restraining aged astrocytes’ maladaptive and neurotoxic preference following injury represents a viable therapeutic strategy to mitigate age-related and injury-induced synaptic and cognitive dysfunction. 

Assistant Professor, Department of Otolaryngology - Head and Neck Surgery, College of Medicine

UK CCTS - Sanders Brown Center on Aging Collaborative Award

Hearing Rehabilitation and the Progression of Cognitive Decline in the Elderly

Professor, Department of Pharmacology and Nutritional Science, College of Medicine

UK CCTS - Barnstable Brown Diabetes and Obesity Center Collaborative Award

Novel role of CD47 in regulating adipose tissue function and energy homeostasis

Obesity and its associated comorbidities are of global concern. Obesity results from an imbalance between energy intake and energy expenditure, leading to excessive storage of spare energy as fat in white adipose tissue (WAT). Current anti-obesity strategies such as restricting energy uptake and exercise are not satisfactory. Therefore, an effective alternative strategy is urgently needed.  Brown adipose tissue (BAT) is a highly metabolically active fat depot. It is characterized by UCP1 positive, mutilocular and thermogenic adipocytes. Unlike WAT to store energy, BAT acts to uncouple respiration to consume energy and produce heat, a process called nonshivering thermogenesis. Recently, functional BAT has been revealed in adult humans and various stimuli could recruit UCP1 positive multilocular adipocytes in WAT (beige). Moreover, numerous studies have shown that activation of BAT increases energy expenditure in rodents and human studies, suggesting that increasing BAT activity and induction of beige formation could be a promising approach to treat obesity. Our preliminary studies identified a previously unrecognized novel role of CD47 in regulating WAT lipolysis and BAT thermogenesis function and its contribution to energy homeostasis and the development of obesity. Further study the mechanisms of CD47’s tissue specific effect on energy homeostasis may lead to novel anti-obesity strategy.

Associate Professor, Pharmacology Nutritional Sciences, College of Medicine

UK CCTS - Barnstable Brown Diabetes and Obesity Center Collaborative Award

Ion Transport in Diabetic Human Hearts

Type-2 diabetes heightens the risk of heart disease, but the underlying mechanisms are poorly understood and there is no specific treatment for heart disease in patients with diabetes. In this pilot project we will utilize human heart tissue that is currently discarded for studies aimed at assessing the role of altered ion transport in diabetic heart disease. Uncovering novel molecular mechanisms involved in the disease will allow us to identify new therapeutic targets for cardioprotection that are specifically tailored to patients with type-2 diabetes.

Associate Professor, Department of Toxicology, College of Medicine

UK CCTS - Markey Cancer Center Collaborative Award

Selective sensitization of head and neck tumors by arsenic trioxide

As the main goal of this project, we have established patient derived tumor xenograft (PDX) of the head and neck oral squamous cell carcinoma (HNSCC). The animal model is applied to study 1) sensitization of HNSCC by novel mechanisms including inhibition of DNA repair by arsenic trioxide and 2) genomic alterations causing acquired resistance of HNSCC against chemoradiotherapy.

Professor of Neuroscience, Department of Anatomy and Neurobiology, College of Medicine

UK CCTS - Spinal Cord and Brain Injury Research Center Collaborative Award

mitoNEET as a Novel Therapeutic Target for TBI

Assistant Professor, Department of Molecular & Cellular Biochemistry, College of Medicine

UK CCTS - Markey Cancer Center & Resource Center for Stable Isotope-Resolved Metabolomics Collaborative Award

Energy Metabolism in Platelets During Thrombus Formatoin

Assistant Professor, Sanders-Brown Center on Aging, College of Medicine

UK CCTS - Sanders Brown Center on Aging Collaborative Award

Rapamycin restores cerebral peripheral vascular and cognitive functions in APOE 4 carriers

This pre-clinical study is to evaluate the potential future usefulness of rapamycin (Rapa) in preventing the development of Alzheimer’s diseases (AD) in subjects that carry the ε4 allele of the apolipoprotein E gene (APOE4). APOE4 is the major genetic risk factor for AD. Individuals that possess one or two APOE4 alleles have a 4- to 8-fold increased risk of developing AD, and the age of onset of AD is reduced by 7–15 years compared to the non-carriers. Cross-sectional studies in healthy APOE4 carriers, who have intact memory, have reported reductions in both regional cerebral blood flow (CBF) in brain regions especially vulnerable to AD pathology. These observations show that the alterations in brain physiology are seen in APOE4 carriers years before any clinical changes occur in memory. We have recently shown that Rapa, an anti-aging intervention, can restore CBF in rodents modeling human AD, and that the CBF elevation was associated with Aβ clearance and enhanced memory. In this proposal, we will extend our investigation to Tg-APOE4 mice. We will use non-invasive neuroimaging methods (e.g., MRI) to measure CBF, and assess memory and learning performance of the mice. We hypothesize that Rapa administered early in disease progression will restore cerebrovascular function and enhance cognitive functions in Tg-APOE4 mice. This research is significant because of its tremendous translation potential — if we were to show that Rapa could reverse the initial phenotype of cerebrovascular dysfunction in Tg-APOE4 mice, we would be in a position to rapidly move to clinical trials in human APOE4 carriers. In addition, the treatment efficacy of Rapa in humans can be monitored over time using the same non-invasive neuroimaging methods used in this study, an excellent strategy for future clinical trials.

Professor, Department of Pathology and Laboratory Medicine, College of Medicine

UK CCTS - Markey Cancer Center & Resource Center for Stable Isotope-Resolved Metabolomics Collaborative Award

Metabolic Pathways Employed by Cancer-Fighting Natural Killer Cells

Natural killer lymphocytes attack cancer cells, but their effectiveness is limited in many tumors. This may be due to the harsh tumor environment, which has low oxygen and low glucose levels. We will investigate natural killer lymphocyte metabolism and study how they meet their energy needs. With this knowledge we may be able to boost particular metabolites or induce particular enzymes that are limiting for natural killer function in tumors.

Assistant Professor, Department of Pharmacy Practice and Science, College of Pharmacy

UK CCTS - Sanders Brown Center on Aging Collaborative Award

Evaluation of a Patient-Centered Medication Therapy Management Intervention to Reduce Inappropriate Anticholinergic Prescribing in the Elderly

Professor, Department of Internal Medicine, College of Medicine

UK CCTS - Markey Cancer Center & Resource Center for Stable Isotope-Resolved Metabolomics Collaborative Award

Systems analysis of blood and vascular cell lipid metabolism responses to atherogenic stimuli

Family history is a strong predictor of cardiovascular disease risk.  The purpose of this study is to understand how heritable variation of a gene encoding a lipid metabolizing enzyme affects cardiovascular disease risk.  Information obtained from mass spectrometry-based studies of lipid metabolism will be integrated with gene expression studies to understand how exposure of a particular type of blood cell responds to a cardiovascular disease promoting stimulus. The results of this study could lead to new approaches for the diagnosis and treatment of cardiovascular disease.

Assistant Professor, Department of Molecular & Cellular Biochemistry, College of Medicine

UK CCTS - Barnstable Brown Diabetes and Obesity Center Collaborative Award

Targeting miR-103/107 for Treatment of Diabetes and Obesity

This project will focus on two miRNAs that have been shown to cause insulin resistance and diabetes.  Using the RIP-ChIP technique, we have identified several mRNA targets for these miRNAs.  The major goal of this pilot grant is to characterize these miRNA targets with regards to their function in insulin-sensitive tissues in order to identify novel drug targets for treatment of diabetes and obesity.

Assistant Professor, Department of Anatomy & Neurobiology, College of Medicine

UK CCTS - Spinal Cord and Brain Injury Research Center Collaborative Award

Flubendazole treatment for spinal cord injury

In this CCTS pilot research entitled “flubendazole treatment for spinal cord injury”, we will evaluate the hypothesis that flubendazole (FluBZ) will attenuate locomotor impairments, secondary damage, pathogenic B cell activation, and astroglial scar formation after contusive spinal cord injury (SCI) in rats. Support of our hypothesis would suggest FluBZ as a novel potential multifunctional therapy for attenuating paralysis after SCI. This compound is clinically approved and could easily be translated to human clinical trials. 

Associate Professor, Department of Nursing, College of Nursing

UK CCTS - Sanders Brown Aging Center Collaborative Award

A Caregiver Cardiac Health Intervention for Dementia Caregivers

The Caregiver Heart Health intervention proposed in this study will address the important components of risk reduction for AD caregivers – most notably depression management and improved self care – using an innovative delivery modality designed to overcome cultural/environmental barriers in austere Appalachian Kentucky. The purpose of this 2-group randomized clinical trial (RCT) is to examine immediate and short-term effects of the Caregiver Heart Health on CVD risk (i.e., lipids, body mass index, blood pressure, waist circumference), self-care healthy behaviors, depression, caregiving burden, and quality of life compared to usual care in family caregivers of persons with AD.

Associate Professor, Department of Chemicals and Materials Engineering, College of Engineering

UK CCTS - Markey Cancer Center Collaborative Award

Pulmonary Targeting of Poly (Curcumin PBAE) Nanoparticles for the Prevention of Radiation Induced Pulmonary Fibrosis

Radiation induced pulmonary pneumonitis remains the dose limiting toxicity associated with lung cancer radiotherapy.  Providing a mechanism to protect healthy tissue while potentiating cancer cells to radiation injury would greatly enhance the effectiveness of radiation treatment, by permitting increased dosing.  Curcumin is a potent antioxidant that has demonstrated the ability to radioprotect lungs against radiation injury, but has poor aqueous solubility and pharmacokinetics that greatly limits its effectiveness.  In this work, we propose to overcome this limitation by developing curcumin loaded nanoparticles targeted to the lung vasculature.

Associate Professor, Department of Pharmaceutical Sciences, College of Pharmacy

UK CCTS - Barnstable Brown Diabetes and Obesity Center Collaborative Award

Ezetimibe & Urso combination therapy in the treatment of nonalcoholic fatty liver disease

Associate Professor, Spinal Cord and Brain Injury Research Center

UK CCTS - Spinal Cord & Brain Research Injury Collaborative Award

Oxidative Damage and Calcium-Activated Proteolytic Biomarkers After Traumatic Brain Injury and Effects of Acute Cyclosporine

This UK CCTS-funded pilot project has two aims. The first is to further explore the clinical utility of biomarkers of neuronal free radical-induced oxidative damage and proteolytic degradation in plasma, urine and/or cerebrospinal fluid (CSF) samples obtained from “severely” injured TBI patients (Glasgow Coma Scale (GCS) = 4-8) and to evaluate whether there is a difference in these in patients with hemorrhagic lesions in their brains compared to patients with diffuse, non-hemorrhagic lesions. The second  second aim is to determine whether acute cyclosporine A treatment within the first 8 hours after TBI in a dose previously suggested to improve outcome in a small phase IIa study  will lessen these markers in parallel with an improvement in the Glasgow Coma Scale (GCS).  If successful, this pilot study will enable development of a larger NIH-funded phase IIb clinical trial of cyclosporine A in which the studied biomarkers will be further evaluated as capable of providing an early signal of neuroprotective drug efficacy.

Associate Professor, Department of Radiation Medicine, College of Medicine

UK CCTS - Markey Cancer Center Collaborative Award

Development of Vimentin Inhibitors for Secretion of Par-4 and Suppression of Tumor Metastasis

Normal cells can be induced to produce robust secretion of tumor suppressor Par-4 protein that targets cancer cells in a paracrine manner. Accordingly, secreted Par-4 is systemically available in vivo and binds to its cell surface receptor GRP78 to trigger apoptosis in primary and metastatic tumors. “Small-molecule” drugs that efficiently and selectively induce Par-4 secretion without killing the normal cells would, therefore, represent an important therapeutic advance. We screened quinolones, thioquinolones and isoquinolines, and identified a new class of “small molecule” secretagogues, called 3-arylquinolines, that promote the desired secretion of Par-4 and identified the molecular target that produces this secretion. We are performing structure-activity relationship (SAR) studies of our lead compounds for robust secretion of Par-4 from normal cells in cell culture and in mice to identify which of these compounds exhibits the potency and efficacy sufficient for paracrine apoptosis of cancer cells and inhibition of EMT/metastasis in mouse tumor models. Developing agents that selectively promote Par-4 secretion from normal cells, induce apoptosis in cancer cells and halt metastatic processes in prostate cancer would be of extraordinary academic and therapeutic value.

Associate Professor, Department of Molecular and Biomedical Pharmacology, College of Medicine

UK CCTS - Markey Cancer Center Collaborative Award

Identify RORa as a Druggable EMT Suppressor

Epithelial-mesenchymal transition (EMT) has been linked with enhanced cell migration, invasion, and high metastatic potential in breast cancer. Identifying druggable EMT regulators and investigating how they inhibit EMT are crucial not only to our understanding of the dynamic EMT process but also to the discovery of potential therapeutic targets for breast cancer. We identified RAR-related orphan nuclear receptor alpha (RORα) as a potent EMT suppressor. The objective of this proposal is to determine activity of RORα agonists in inhibiting EMT and breast cancer metastasis and to delineate the molecular mechanisms by which RORα inhibits EMT. We have compelling data showing that RORα is an EMT suppressor and involved in cancer metastasis. But how RORα suppresses the EMT process and whether RORα agonists inhibit EMT and cancer metastasis have not been determined. The central hypothesis of our proposal is that RORα inhibits EMT process by reducing Snail expression, and that RORα agonists inhibit breast cancer metastasis by suppressing EMT. To test our central hypothesis and achieve the objective of this proposal, we have designed experiments with the following specific aims: Aim 1: To elucidate the molecular mechanism by which RORα inhibits EMT. Aim 2: To determine the biological activity of RORα agonists in inhibiting EMT and breast cancer metastasis.

Associate Professor, Department of Physical Medicine and Rehabilitation, College of Medicine

UK CCTS- Spinal Cord & Brain Injury Research Collaborative Award

Effects of Trans-Vertebral Direct Current Stimulation In Humans

According to the National Spinal Cord Injury Statistical Center, as many as 300,000 people in the United States are living with spinal cord injury (SCI). Approximately 12,000 new cases of SCI occur each year in the United States. It has not yet been discovered how to limit damage in early stages of SCI. Therefore, it is important to find ways to enhance motor recovery in SCI survivors over the long term. A considerable amount of evidence shows that noninvasive forms of brain stimulation can promote recovery of motor function in neurological populations, including SCI. Limited data exists regarding similar strategies to stimulate the spinal cord, but evidence in this regard is promising. To expand on this evidence, we will study transvertebral direct current stimulation, or tvDCS. In tvDCS, we apply mild, painless electrical stimulation to the spinal cord through electrodes placed on the back. Our experiment will help us determine if tvDCS makes the spinal cord more receptive to motor training and gait rehabilitation. We will study tvDCS in healthy subjects without SCI, and then, in subjects with SCI. This design will allow us to establish strong, basic science data prior to rapid clinical application of our findings. This unique, groundbreaking work represents the cutting edge of advanced technology-based strategies to restore function and enhance quality of life for SCI survivors.

Associate Professor, Department of Graduate Center for Nutritional Sciences, College of Medicine

UK CCTS - Barnstable Brown Diabetes and Obesity Center Collaborative Award

IKK Beta Links Vascular Inflammation to Obesity and Insulin Resistance

Obesity is associated with a state of chronic low-grade inflammation that has been considered to be a major contributor to diabetes and atherosclerosis. The goal of this project is to investigate the role of IκB kinase β (IKKβ), a central coordinator of innate immunity and inflammation through activation of NF-κB, in linking vascular inflammation with adipogenesis and obesity.  With the support from the CCTS pilot program, we recently demonstrated, for the first time, that IKKβ functions in adipocyte precursor cells to regulate adipogenesis and adipose tissue development.  We also provided strong evidence for use of appropriate IKKβ inhibitors as an innovative therapeutic strategy to treat obesity and metabolic disease.

Associate Professor, Department of Physiology, College of Medicine

UK CCTS - Barnstable Brown Diabetes and Obesity Center Collaborative Award

Realigning circadian rhythms to improve health

Professor, Department of Molecular & Cellular Biochemistry, College of Medicine

UK CCTS - Markey Cancer Center Collaborative Award

Pilot Studies to develop small-molecule inhibitors of cancer cell migration and invasion

Assistant Professor, Sanders Brown Center on Aging, College of Medicine

UK CCTS - Sanders Brown Center on Aging Collaborative Award

Role of peroxisome proliferator-activated receptors (PPARs) on the regulation of microRNAs in neuronal cells