Translational Medical Research Commons^™

Mitochondria As Causes Of And Therapeutic Targets In Chronic Post-Sepsis Skeletal Muscle Weakness, Meagan Scott Kingren

Theses and Dissertations--Pharmacology and Nutritional Sciences

Sepsis, or the organ damage that ensues after the body fails to properly contain a local infection, is the leading cause of in-patient hospitalization in the United States. Advances in critical care medicine over the last 20 years have enabled most sepsis patients to survive the life-threatening dysregulated immune response. However, a majority of survivors report chronic weakness and fatigue years after sepsis, and the cause of this weakness remains largely unknown. This dissertation work focused first on elucidating the major causes of post-sepsis muscle weakness (Aim 1). This aim involved a time-course study to determine when muscle weakness was …

Assessment Of The Interplay Between Regional Β-Amyloid Burden And White Matter Hyperintensities On Cognition And Default Mode Network In Clinically Normal Older Participants, Doaa G. Ali

Theses and Dissertations--Clinical and Translational Science

Objective: Alzheimer’s disease (AD) and subcortical vascular dementia are considered the most common pathologic contributors to dementia in the aging population. Both frequently coexist in over 80% of community dwelling adults with dementia. The neuropathological development of AD arguably begins with β-amyloid (Aβ) deposition in the brain. This series of studies aims to test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in preclinical AD (pAD) (study1). Since mixed dementia is widely recognized as the norm rather than the exception, the second study aimed to explore the …

Alzheimer’S Disease Genetics And Short-Chain Fatty Acid Treatment In Studies Of The Murine Gut Microbiome, Diana Zajac

Theses and Dissertations--Physiology

Elucidating the relationship of the gut microbiome in Alzheimer's Disease (AD) risk and pathogenesis is an area of intense interest. Since 60 to 80% of AD risk is related to genetics and APOE alleles represent the most impactful genetic risk factors for AD, their mechanism(s) of action are under intense scrutiny.

First, I conducted a study on APOE targeted replacement mice to investigate the impact of APOE alleles on the murine gut microbiome. The relative abundance of bacteria from the family Ruminococacceae and related genera increased with APOE2 status. The relative abundance of the class Erysipelotrichia increased with APOE4 status, …

Potential Benefits Of Combined Statin And Metformin Therapy On Resistance Training Response In Older Individuals, Douglas E. Long, Kate Kosmac, Cory M. Dungan, Marcas M. Bamman, Charlotte A. Peterson, Phillip A. Kern

Clinical and Translational Science Faculty Publications

Metformin and statins are currently the focus of large clinical trials testing their ability to counter age-associated declines in health, but recent reports suggest that both may negatively affect skeletal muscle response to exercise. However, it has also been suggested that metformin may act as a possible protectant of statin-related muscle symptoms. The potential impact of combined drug use on the hypertrophic response to resistance exercise in healthy older adults has not been described. We present secondary statin analyses of data from the MASTERS trial where metformin blunted the hypertrophy response in healthy participants (>65 years) following 14 weeks …

Evaluating Simulation-Based Tobacco Treatment Scenarios For Providers Delivering Treatment For People Living With Mental Illnesses, Chizimuzo T. C. Okoli, Janet Otachi, Sarret Seng, Bassema Abufarsakh, Lovoria B. Williams

Clinical and Translational Science Faculty Publications

Background: People living with mental illnesses (PMI) experience elevated tobacco use and related morbidity and mortality. Despite the availability of effective and safe tobacco treatments along with evidence that PMI are motivated and able to quit successfully, few Mental and behavioral healthcare providers (MHPs) engage PMI in such treatment. MHPs may lack the confidence or skills to engage their clients in tobacco treatment. Currently, there are limited training modalities to prepare MHPs in delivering tobacco treatment for PMI. However, animated scenario-based simulated encounters can bridge this gap to effectively provide tailored MHP training to enhance treatment delivery. Hence, the purpose …

Tumor Suppressor Par-4 Regulates Complement Factor C3 And Obesity, Nathália Araujo, James Sledziona, Sunil K. Noothi, Ravshan Burikhanov, Nikhil Hebbar, Saptadwipa Ganguly, Tripti Shrestha-Bhattarai, Beibei Zhu, Wendy S. Katz, Yi Zhang, Barry S. Taylor, Jinze Liu, Li Chen, Heidi L. Weiss, Daheng He, Chi Wang, Andrew J. Morris, Lisa A. Cassis, Mariana N. Nikolova‑Karakashian, Prabhakara R. Nagareddy, Olle Melander, B. Mark Evers, Phillip A. Kern, Vivek M. Rangnekar

Clinical and Translational Science Faculty Publications

Prostate apoptosis response-4 (Par-4) is a tumor suppressor that induces apoptosis in cancer cells. However, the physiological function of Par-4 remains unknown. Here we show that conventional Par-4 knockout (Par-4^-/-) mice and adipocyte-specific Par-4 knockout (AKO) mice, but not hepatocyte-specific Par-4 knockout mice, are obese with standard chow diet. Par-4^-/- and AKO mice exhibit increased absorption and storage of fat in adipocytes. Mechanistically, Par-4 loss is associated with mdm2 downregulation and activation of p53. We identified complement factor c3 as a p53-regulated gene linked to fat storage in adipocytes. Par-4 re-expression in adipocytes or c3 deletion reversed …

Regulatory T Cells Control Effector T Cell Inflammation In Human Prediabetes, Rui Liu, Gabriella H. Pugh, Erin Tevonian, Katherine Thompson, Douglas A. Lauffenburger, Philip A. Kern, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest …

Regulation Of Skeletal Muscle Plasticity By The Gut Microbiome, Taylor R. Valentino

Theses and Dissertations--Physiology

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight …

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Clinical and Translational Science Faculty Publications

Background: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

Methods: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

Adult Spiny Mice (Acomys) Exhibit Endogenous Cardiac Recovery In Response To Myocardial Infarction, Hsuan Peng, Kazuhiro Shindo, Renée R. Donahue, Erhe Gao, Brooke M. Ahern, Bryana M. Levitan, Himi Tripathi, David Powell, Ahmed Noor, Garrett A. Elmore, Jonathan Satin, Ashley W. Seifert, Ahmed K. Abdel-Latif

Physiology Faculty Publications

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). While Acomys species exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baseline Acomys cardiac anatomy and function in comparison with commonly used inbred and outbred laboratory Mus strains (C57BL6 and CFW). While our results demonstrated comparable cardiac anatomy and function between Acomys and Mus, Acomys exhibited a higher percentage of cardiomyocytes displaying …

Development Of A Novel Mir-3648-Related Gene Signature As A Prognostic Biomarker In Esophageal Adenocarcinoma, Donglei Zhang, Hang Yin, Thomas L. Bauer, Michael P. Rogers, Jeffrey B. Velotta, Clinton T. Morgan, Weijia Du, Ping Xu, Xiaozhe Qian

Surgery Faculty Publications

Background: Esophageal adenocarcinoma (EA) is a typical immunogenic malignant tumor with a dismal 5-year survival rate lower than 20%. Although miRNA-3648 (miR-3648) is expressed abnormally in EA, its impact on the tumor immune microenvironment remains unknown. In this study, we sought to identify immune-related genes (IRGs) that are targeted by miR-3648 and develop an EA multigene signature.

Methods: The gene expression data of 87 EA tumor samples and 67 normal tissue samples from The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database were downloaded, respectively. Weighted gene co-expression network analysis (WGCNA), the CIBERSORT algorithm, and Cox regression …

Apoε4 Lowers Energy Expenditure In Females And Impairs Glucose Oxidation By Increasing Flux Through Aerobic Glycolysis, Brandon C. Farmer, Holden C. Williams, Nicholas A. Devanney, Margaret A. Piron, Grant K. Nation, David J. Carter, Adeline E. Walsh, Rebika Khanal, Lyndsay E. A. Young, Jude C. Kluemper, Gabriela Hernandez, Elizabeth J. Allenger, Rachel Mooney, Lesley R. Golden, Cathryn T. Smith, J. Anthony Brandon, Vedant A. Gupta, Philip A. Kern, Matthew S. Gentry, Josh M. Morganti, Ramon C. Sun, Lance A. Johnson

Physiology Faculty Publications

BACKGROUND: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.

METHODS: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.

RESULTS: Single-cell …

Covid-19 And The Impact On Rural And Black Church Congregants: Results Of The C-M-C Project, Lovoria B. Williams, Anita F. Fernander, Tofial Azam, Maria L. Gomez, Junghee Kang, Cassidy L. Moody, Hannah Bowman, Nancy E. Schoenberg

Clinical and Translational Science Faculty Publications

The COVID‐19 pandemic has had devastating effects on Black and rural populations with a mortality rate among Blacks three times that of Whites and both rural and Black populations experiencing limited access to COVID‐19 resources. The primary purpose of this study was to explore the health, financial, and psychological impact of COVID‐19 among rural White Appalachian and Black nonrural central Kentucky church congregants. Secondarily we sought to examine the association between sociodemographics and behaviors, attitudes, and beliefs regarding COVID‐19 and intent to vaccinate. We used a cross sectional survey design developed with the constructs of the Health Belief and Theory …

Utilizing Patient-Derived Epithelial Ovarian Cancer Tumor Organoids To Predict Carboplatin Resistance, Justin W. Gorski

Theses and Dissertations--Clinical and Translational Science

The development of patient-derived tumor organoids (TOs) from epithelial ovarian cancer tumor obtained at the time of primary or interval debulking surgery has the potential to play an important role in precision medicine.

Here, we utilize TOs to test front-line chemotherapy sensitivity and to investigate genomic drivers of carboplatin resistance. We developed six high grade serous epithelial ovarian cancer tumor organoids from tissue obtained during debulking surgery (2 neoadjuvant carboplatin exposed, 4 chemo-naïve). Each organoid line was screened for sensitivity to carboplatin at four different doses (100, 10, 1 and 0.1µM). Cell viability curves and resultant EC50 values were determined …

Human Regulatory T Cells Control Inflammation From Effector T Cells In Prediabetes, Rui Liu

Theses and Dissertations--Pharmacy

Type 2 diabetes (T2D) is a chronic low-grade inflammatory disease. A T cell cytokine profile (Th17) from PBMCs can distinguish obese T2D from obese non-diabetes subjects. Individual T cell subsets interact with each other and the diverse subsets jointly determine overall inflammation. Cellular metabolism drives cytokine production of CD4⁺ T cells, and therefore contributes to inflammation in T2D. However, specific changes in metabolism and function of CD4⁺ T cells during the progression from lean healthy to obese and diabetic stages in people have not been clarified.

We hypothesize that human regulatory T cells (Treg) impact metabolism of effector …

The Use Of Mechanotherapy To Promote The Recovery From Disuse Atrophy In Aging Rat Skeletal Muscle, Zachary Hettinger

Theses and Dissertations--Rehabilitation Sciences

The combination of age and disuse-related skeletal muscle atrophy predisposes older adults to reduced mobility, loss of independence, and poor quality of life. Poor health outcomes resulting from periods of disuse in older adults are exacerbated by an inability to fully recover, ultimately accelerating geriatric populations towards further functional decline. Aged-related changes to skeletal muscle viscoelastic properties, specifically of muscle extracellular matrix (ECM) stiffness, may not only impact how muscle responds during recovery, but also to interventions intended to augment recovery. Remodeling of muscle ECM in the aged may therefore benefit muscle mass recovery, yet therapies focused on ECM remodeling …

Metformin Enhances Autophagy And Normalizes Mitochondrial Function To Alleviate Aging-Associated Inflammation, Leena P. Bharath, Madhur Agrawal, Grace Mccambridge, Dequina A. Nicholas, Hatice Hasturk, Jing Liu, Lao Jiang, Rui Liu, Zhenheng Guo, Jude T. Deeney, Caroline M. Apovian, Jennifer Snyder-Cappione, Gregory S. Hawk, Rebecca M. Fleeman, Riley M. F. Pihl, Katherine Thompson, Anna C. Belkina, Licong Cui, Elizabeth A. Proctor, Philip A. Kern, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 …

Knee Joint Loading Following Anterior Cruciate Ligament Reconstruction: Link To Patient Reported Outcomes And A Novel Method To Monitor With Wearable Sensors, Alex Spencer

Theses and Dissertations--Kinesiology and Health Promotion

Recovery from anterior cruciate ligament reconstruction (ACLR) commonly results in undesirable physical and patient-reported outcomes (PROs). Identification of modifiable factors such as knee contact force (KCF) early in rehabilitation that can improve these outcomes is important due to the rapid decrease in function, quality of life, and joint health in this population. Additionally, if noninvasive measurement of KCFs outside of a traditional laboratory were possible, clinicians could optimize patient treatment with personalized care. Therefore, there are two primary aims to this thesis: 1) quantify the link between KCF and PROs which measure pain, ability to perform activities of daily living, …

Atv Dynamics And Pediatric Rider Safety, James T. Auxier Ii

Theses and Dissertations--Biomedical Engineering

It has been observed through numerous academic and governmental agency studies that pediatric all-terrain vehicle ridership carries significant risk of injury and death. While no doubt valuable to safety, the post-hoc approach employed in these studies does little to explain the why and how behind the risk factors. Furthermore, there has been no prolonged, widespread, organized, and concerted effort to reconstruct and catalog the details and causes of the large (20,000+) number of ATV-related injuries that occur each year as has been done for road-based motor vehicle accidents. This dissertation takes the opposite approach from a meta-analysis and instead examines …

Transcriptomic And Cellular Response To Mechanical Overload And The Underlying Role Of Macrophages In Extracellular Matrix Remodeling, Bailey D. Peck

Theses and Dissertations--Rehabilitation Sciences

The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. Upon mechanical loading, including resistance exercise, which alter muscle fiber contractile activity, size, orientation and connectivity, remodeling processes must occur that involve both ECM deposition and degradation. ECM remodeling involves many cell types in muscle, but the focus of our research was directed towards macrophages, which participate in the early immune response to damage and loading. We have consistently demonstrated a significant increase in skeletal muscle macrophage abundance using pan macrophage markers (CD11b/CD68) and anti-inflammatory markers (CD206/CD163) following exercise training in …

The Value Of Innovation To Implementation Program (Vi2p): A Strategic Approach To Aligning And Leveraging Academic Research And Clinical Care Missions, Jing Li, Mark V. Williams, Cecilia Page, Lisa A. Cassis, Philip A. Kern, Robert S. Dipaola

Clinical and Translational Science Faculty Publications

Problem: Inefficient implementation of evidence-based care garners increasing attention as a source of suboptimal value of clinical care, and integration of quality improvement methodology into clinical practice represents a potential solution. Academic medical centers (AMCs) often have expertise in implementation science, yet it is not leveraged effectively to solve operational inefficiencies or to rapidly implement evidence-based practices (EBPs).

Approach: To leverage in-house research expertise, the University of Kentucky (UK) College of Medicine and Center for Health Services Research (CHSR) launched a pilot awards program—Value of Innovation to Implementation Program (VI2P)—across its health system and six health professional colleges. Criteria for …

Metformin Blunts Muscle Hypertrophy In Response To Progressive Resistance Exercise Training In Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial: The Masters Trial, R. Grace Walton, Cory M. Dungan, Douglas E. Long, S. Craig Tuggle, Kate Kosmac, Bailey D. Peck, Heather M. Bush, Alejandro G. Villasante Tezanos, Gerald Mcgwin, Samuel T. Windham, Fernando Ovalle, Marcas M. Bamman, Philip A. Kern, Charlotte A. Peterson

Clinical and Translational Science Faculty Publications

Progressive resistance exercise training (PRT) is the most effective known intervention for combating aging skeletal muscle atrophy. However, the hypertrophic response to PRT is variable, and this may be due to muscle inflammation susceptibility. Metformin reduces inflammation, so we hypothesized that metformin would augment the muscle response to PRT in healthy women and men aged 65 and older. In a randomized, double-blind trial, participants received 1,700 mg/day metformin (N = 46) or placebo (N = 48) throughout the study, and all subjects performed 14 weeks of supervised PRT. Although responses to PRT varied, placebo gained more lean body …

Fatty Acid Metabolites Combine With Reduced Β Oxidation To Activate Th17 Inflammation In Human Type 2 Diabetes, Dequina A. Nicholas, Elizabeth A. Proctor, Madhur Agrawal, Anna C. Belkina, James M. Van Nostrand, Leena Panneerseelan-Bharath, Albert R. Jones Iv, Forum Raval, Blanche C. Ip, Min Zhu, Jose M. Cacicedo, Chloe Habib, Nestor Sanez-Rueda, Leah Persky, Patrick G. Sullivan, Barbara E. Corkey, Caroline M. Apovian, Philip A. Kern, Douglas A. Lauffenburger, Barbara S. Nikolajczyk

Clinical and Translational Science Faculty Publications

Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for …

Quantitative Systems Pharmacology Model Of Chimeric Antigen Receptor T-Cell Therapy, Deni Hardiansyah, Chee Meng Ng

Pharmaceutical Sciences Faculty Publications

Chimeric antigen receptor T‐cell (CART) therapy is a new and promising cancer therapy. However, severe toxicity due to cytokine release syndrome (CRS) in CART‐treated patients highlighted the possible danger of this new therapy. Disease burden and CART doses are the potential factors associated with CRS but the detail relationships between these factors and the severity of the CRS remain largely unknown. In this study, the quantitative systems pharmacology (QSP) approach is used to quantify the complex relationships among CART doses, disease burden, and pro inflammatory cytokines in human subjects and to gain relevant insights into the determinant of clinical toxicity/efficacy …

Sphk2−/− Mice Are Protected From Obesity And Insulin Resistance, Shwetha Ravichandran, Brian S. Finlin, Philip A. Kern, Sabire Özcan

Clinical and Translational Science Faculty Publications

Sphingosine kinases phosphorylate sphingosine to sphingosine 1‑phosphate (S1P), which functions as a signaling molecule. We have previously shown that sphingosine kinase 2 (Sphk2) is important for insulin secretion. To obtain a better understanding of the role of Sphk2 in glucose and lipid metabolism, we have characterized 20- and 52-week old Sphk2^−/− mice using glucose and insulin tolerance tests and by analyzing metabolic gene expression in adipose tissue. A detailed metabolic characterization of these mice revealed that aging Sphk2^−/− mice are protected from metabolic decline and obesity compared to WT mice. Specifically, we found that 52-week old …

A Guide For Using Nih Image J For Single Slice Cross-Sectional Area And Composition Analysis Of The Thigh From Computed Tomography, Douglas E. Long, Alejandro G. Villasante Tezanos, James N. Wise, Phillip A. Kern, Marcas M. Bamman, Charlotte A. Peterson, Richard A. Dennis

Clinical and Translational Science Faculty Publications

Reports using computed tomography (CT) to estimate thigh skeletal muscle cross-sectional area and mean muscle attenuation are often difficult to evaluate due to inconsistent methods of quantification and/or poorly described analysis methods. This CT tutorial provides step-by-step instructions in using free, NIH Image J software to quantify both muscle size and composition in the mid-thigh, which was validated against a robust commercially available software, SliceOmatic. CT scans of the mid-thigh were analyzed from 101 healthy individuals aged 65 and older. Mean cross-sectional area and mean attenuation values are presented across seven defined Hounsfield unit (HU) ranges along with the percent …

A Brain-Computer Interface For Closed-Loop Sensory Stimulation During Motor Training In Patients With Tetraplegia, Sarah Helen Thomas

Theses and Dissertations--Biomedical Engineering

Normal movement execution requires proper coupling of motor and sensory activation. An increasing body of literature supports the idea that incorporation of sensory stimulation into motor rehabilitation practices increases its effectiveness. Paired associative stimulation (PAS) studies, in which afferent and efferent pathways are activated in tandem, have brought attention to the importance of well-timed stimulation rather than non-associative (i.e., open-loop) activation. In patients with tetraplegia resulting from spinal cord injury (SCI), varying degrees of upper limb function may remain and could be harnessed for rehabilitation. Incorporating associative sensory stimulation coupled with self-paced motor training would be a means for supplementing …

Integrin Α5Β1 As A Novel Target With The Small Peptide, Atn-161, In The Treatment Of Ischemic Stroke, Danielle Nichele Edwards

Theses and Dissertations--Neuroscience

Stroke is the 5^th leading cause of death and the leading cause of disability in the United States, but there are only two available therapies, tissue plasminogen activator and endovascular thrombectomy. As both therapies focus on removal of the clot, the subsequent pathologic processes, i.e. inflammation, cerebrovascular breakdown, ATP depletion, etc. are left untreated, contributing to worsened patient outcome. Many clinical trials have unsuccessfully attempted to address these mechanisms. The blood-brain barrier (BBB), a system of non-fenestrated endothelial cells, extracellular matrix, and astrocytic endfeet, is significantly impacted after ischemic stroke in its role of preventing the free movement of …

Development Of Mithramycin Analogues With Improved Efficacy And Reduced Toxicity For Treatment Of Ets-Dependent Tumors In Ewing Sarcoma And Prostate Cancer, Joseph Michael Eckenrode

Theses and Dissertations--Pharmacy

Introduction: Genetic rearrangements in Ewing sarcoma, prostate, and leukemia cells result in activation of oncogenic ETS transcription factor fusions. Mithramycin (MTM) has been identified as an inhibitor of EWS-FLI1 transcription factor, a gene fusion product responsible for oncogenesis in Ewing sarcoma. Despite preclinical success, a phase I/II clinical trial testing MTM therapy in refractory Ewing sarcoma was terminated. Liver and blood toxicities resulted in dose de-escalation and sub-therapeutic exposures. However, the promise of selectively targeting oncogenic ETS transcription factors like EWS-FLI1 prompted us to undertake the discovery of more selective, less toxic analogues of MTM. MTM is a potent inhibitor …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …