Digital Commons Network^™

Identification Of Infant Feeding Practices In Eastern Kentucky And Southern West Virginia That Correlate With High Weight-For-Length, Havilah R. Adkins

DNP Projects

Background: Approximately 20% of children in the United States are obese. West Virginia and Kentucky rank in the top 10 for obesity rates in children as young as 2-4 years old. Obesity increases the risk for numerous short-term health problems and impacts long-term health, development, quality of life, and life expectancy. Research indicates that obesogenic behaviors can be addressed prior to the development of obesity or significant health problems to prevent, rather than treat. Interventions targeting caregivers of infants younger than 2-years can promote early development of healthy feeding habits that persist through the developmental stages of nutrition. Before a …

Osteocyte Activity And Skeletal Muscle Relative Gene Expression Profiling After Short-Term Muscle Paralysis, Michelle Gelbs

Dissertations and Theses

Mechanical loading is essential for maintaining bone tissue. Reduced mechanical loading has been shown to have a negative effect on bone, and can result in the development of disuse osteoporosis. Disuse models of muscle inactivity and immobilization, like the Botox model used in this study, result in changes in the bone microarchitecture, the mechanisms behind which are not fully understood. In a previous four-week Botox disuse study, skeletally mature 20- week-old rats experienced degradation of intracortical bone, increased vascular porosity, and decreased osteocyte lacunar density in the tibiae. The focus of this study was to explicate a potential source of …

Development Of Light Actuated Chemical Delivery Platform On A 2-D Array Of Micropore Structure, Hojjat Rostami Azmand, Hojjat Rostami Azmand

Dissertations and Theses

Localized chemical delivery plays an essential role in the fundamental information transfers within biological systems. Thus, the ability to mimic the natural chemical signal modulation would provide significant contributions to understand the functional signaling pathway of biological cells and develop new prosthetic devices for neurological disorders. In this paper, we demonstrate a light-controlled hydrogel platform that can be used for localized chemical delivery in a high spatial resolution. By utilizing the photothermal behavior of graphene-hydrogel composites confined within micron-sized fluidic channels, patterned light illumination creates the parallel and independent actuation of chemical release in a group of fluidic ports. The …

Association Of Palb2 Variants With Risk To Breast Cancer And Molecular Characterisation Of Palb2 Tumours, Ng Pei Sze

Student Works (2020-2029)

Purpose: Germline rare protein truncating variants (PTVs) in PALB2 are associated with an increased risk to breast cancer. At present, most of the available data on genetic predisposition to breast cancer are derived from studies in women of European descent, and it is unclear the extent to which population-specific differences in genetic and lifestyle factors may contribute to differences in lifetime risk to breast cancer in women of other ancestries. This study sought to determine the prevalence of, mutation spectrum in and the risk estimates associated with PALB2 in a multiethnic cohort of 7840 breast cancer cases and 7928 healthy …

Mucins, Gut Microbiota, And Postbiotics Role In Colorectal Cancer, Ramesh Pothuraju, Sanjib Chaudhary, Satyanarayana Rachagani, Sukhwinder Kaur, Hemant K Roy, Michael Bouvet, Surinder K Batra

Faculty, Staff and Students Publications

An imbalance in the crosstalk between the host and gut microbiota affects the intestinal barrier function, which results in inflammatory diseases and colorectal cancer. The colon epithelium protects itself from a harsh environment and various pathogenic organisms by forming a double mucus layer, primarily comprising mucins. Recent studies are focusing on how dietary patterns alter the gut microbiota composition, which in turn regulates mucin expression and maintains the intestinal layers. In addition, modulation of gut microbiota by microbiotic therapy (involving fecal microbiota transplantation) has emerged as a significant factor in the pathologies associated with dysbiosis. Therefore, proper communication between host …

Small-Molecule Inhibitor Of Af9/Enl-Dot1l/Af4/Aff4 Interactions Suppresses Malignant Gene Expression And Tumor Grow, Fangrui Wu, Shenyou Nie, Yuan Yao, Tong Huo, Xin Li, Xiaowei Wu, Jidong Zhao, Yi-Lun Lin, Yinjie Zhang, Qianxing Mo, Yongcheng Song

Faculty, Staff and Students Publications

Chromosome translocations involving mixed lineage leukemia (MLL) gene cause acute leukemia with a poor prognosis. MLL is frequently fused with transcription cofactors AF4 (~35%), AF9 (25%) or its paralog ENL (10%). The AHD domain of AF9/ENL binds to AF4, its paralog AFF4, or histone-H3 lysine-79 (H3K79) methyltransferase DOT1L. Formation of AF9/ENL/AF4/AFF4-containing super elongation complexes (SEC) and the catalytic activity of DOT1L are essential for MLL-rearranged leukemia. Protein-protein interactions (PPI) between AF9/ENL and DOT1L/AF4/AFF4 are therefore a potential drug target.

Methods: Compound screening followed by medicinal chemistry was used to find inhibitors of such PPIs, which were examined for their biological …

Molecular Basis Of Cross-Sensitization In Colonic Inflammation-Induced Somatic Hypersensitivity, Parshva K. Mehta

Theses and Dissertations

A major portion of pain experienced by patients with an Irritable Bowel Disease (IBD) or Irritable Bowel Syndrome (IBS) can be attributed to visceral hypersensitivity. Visceral stimuli transmitted through primary afferent neurons in the dorsal root ganglia (DRG) induce a nociceptive response. Notably, a subset of patients has also experienced the development of somatic pain, such as leg pain, after diagnosis of a bowel disorder. The aim of this investigation is to ascertain which biochemical mediators are involved in the development of such viscerosomatic cross-sensitization. Initially, the Von Frey Test was used to find behavioral evidence of somatic referred pain; …

Role Of P53 Deficient Clonogenic Endothelial Cells In The Pathogenesis Of Pulmonary Hypertension, Aneel Roy Bhagwani

Theses and Dissertations

Pulmonary Artery Hypertension (PAH) is a progressive disorder of the small vessels of the pulmonary vasculature. It is characterized by occlusive vascular remodeling leading to right heart failure and ultimately death. PAH pathogenesis involves a multifactorial etiology leading to formation of occlusive lesions in small (preacinary) pulmonary arteries. These lesions contain hyper-proliferative, apoptosis resistant endothelial cells (ECs), smooth muscle cells and fibroblasts. ECs play a major role in the development of PAH. These ECs in vascular lesions are primitive and express progenitor cell markers, including CD117 (c-kit).

We have isolated clonally expanded, c-kit+ ECs from the lungs of Green Fluorescent …

Glycosaminoglycan Modulation Of Key Proteins In Alzheimer's Disease, Tamim Chiba

Theses and Dissertations

Glycosaminoglycans (GAGs) are linear polysaccharides whose disaccharide building blocks consist of an amino sugar (D-glucosamine) and either uronic acid (D-glucuronic acid or L-iduronic acid) or galactose. Nearly all GAGs (with the exception of hyaluronic acid) are covalently attached to proteins, forming proteoglycans, and are ubiquitous in nature. The monomeric units, chain length, degree and pattern of sulfation, and epimerization are important properties that determine the influence of these molecules. Through Coulombic forces, hydrogen bonds and hydrophobic interactions, they regulate many physiological and pathophysiological processes such as blood coagulation, cell growth and differentiation, inflammatory processes, host defense and viral infection mechanisms. …

Vasopressin Regulates Daily Rhythms And Circadian Clock Circuits In A Manner Influenced By Sex, Kayla Rohr, Adam Telega, Alexandra Savaglio, Jennifer A. Evans

Biomedical Sciences Faculty Research and Publications

Arginine vasopressin (AVP) is a neurohormone that alters cellular physiology through both endocrine and synaptic signaling. Circadian rhythms in AVP release and other biological processes are driven by the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Loss of vasopressin signaling alters circadian behavior, but the basis of these effects remains unclear. Here we investigate the role of AVP signaling in circadian timekeeping by analyzing behavior and SCN function in a novel AVP-deficient mouse model. Consistent with previous work, loss of AVP signaling increases water consumption and accelerates recovery to simulated jetlag. We expand on these results to show that loss …

Experience-Dependent Plasticitiy Of Functional Connectivity In Human Visual Cortex Following Central Vision Loss, Leland Lanelle Fleming

All ETDs from UAB

The human brain is shaped by a dynamic interplay between innate factors and life experiences. Neuroscience has long grappled with understanding this relationship, particularly with regard to how changes in experience impact the brain during adulthood. This question is especially important in the context of macular degeneration, a disease that causes significant visual impairment and drastically alters day-to-day visual experiences for individuals afflicted by the disease. Specifically, people with macular degeneration lose the ability to use vision in the center of the visual field, the region of the retina with the highest spatial resolution. Subsequently, these individuals must rely on …

Regulation Of Nitric Oxide Syntahse 3 By Histone Deacetylase, Luke S. Dunaway

All ETDs from UAB

In the vasculature, nitric oxide is produced by nitric oxide synthase 3 (NOS3) and protects against the development of cardiovascular disease (CVD). The histone deacetylases (HDACs) are a family of enzymes responsible for lysine deacetylation of both histone and non-histone proteins. Understanding how NO signaling is regulated by HDACs will allow us to better understand how HDAC inhibitors may be of use in treating CVD. This dissertation seeks to provide novel insight into the regulation of NOS3 by this family of enzymes. Endothelial NO production is impaired in human subjects and rodents fed a high salt diet (HS). We have …

The Impact Of Blimp1 On Etreg Stability And The Tumor Microenvironment, Michael Dixon

All ETDs from UAB

CD4+ Foxp3+ regulatory T (Treg) cells are responsible for maintaining immunological homeostasis and self-tolerance through the regulation of immune responses against foreign and self-antigens, and they comprise both central Treg and effector Treg (eTreg) subsets. Because of their ability to suppress potent immune responses, eTreg cells expressing the transcription factor Blimp1 are frequently recruited to the tumor microenvironment (TME) to suppress anti-tumor responses by tumor infiltrating effector cells. Here, we demonstrate in murine transplantable tumor models that Blimp1 is required for intratumoral eTreg stability and that loss of Blimp1 by intratumoral eTreg cells results in their reduced suppressive activity and …

Studies On Nontypeable Haemophilus Influenzae Biofilm Persistence & Redox Homeostasis In Chronic Bacterial Diseases, Benjamin C. Hunt

All ETDs from UAB

Bacterial biofilms, or surface-adherent bacterial communities surrounded by a self-produced extracellular polymeric matrix, are ubiquitous. They are found throughout Earth’s ecosystems, in the soil and waterways, and more pressingly for the medical community, they are found within humans. Bacterial biofilms are associated with a multitude of diseases and their involvement significantly complicates treatment given that bacteria growing within a biofilm are extremely more resistant to antibiotics and immune effectors. Thus, the need to better understand biofilm biology and find ways to disrupt and/or sensitize biofilms to medical treatment is significant. The goal of the research presented herein was to investigate …

Diurnal Variation In Hippocampal Neurophysiology And Pathophysiology, Allison R. Fusilier

All ETDs from UAB

Circadian rhythms are ~24-hour cycles in biological processes that are endogenously generated, entrained to light, and synchronized by the suprachiasmatic nucleus of the hypothalamus. One process that is influenced by circadian rhythms is cognitive function, which varies over the course of the day and is likely influenced by changes in neuronal physiology over the course of the day. Dysfunction in circadian rhythms has been documented in many diseases, including Alzheimer’s disease (AD). AD is a neurodegenerative disease most notably characterized by dementia, amyloid beta plaques, and tau tangles. There is currently no cure for AD, and treatments only slow disease …

Effeccts Of Hiv-1 Tat On Tspo, A Biomarker Of Neuroinflammation, Nguyen Thuy Nhu Nguyen

All ETDs from UAB

HIV-associated neurocognitive disorders (HAND) produces serious neurological dysfunction for > 50% of people living with HIV (PLWH). As antiretroviral therapy (ART) has transformed HIV into a chronic disease, and since most ART does not effectively cross the blood brain barrier, HAND is predicted to further increase in prevalence in PLWH. The HIV-Trans-Activator of Transcription (Tat) is known to persist in the central nervous system (CNS) of chronically infected HIV+ individuals. In several preclinical studies, HIV-Tat has been shown to be neurotoxic and important for HIV pathogenesis. Translocator protein (TSPO), an 18 kDa mitochondrial protein, has been shown to be increased via …

Characterization Of Rna Polymerase I Trigger Loop Mutations, Collin Ainslie

All ETDs from UAB

RNA polymerases are primarily multi-subunit enzymes that synthesize RNAs from template DNA strands. RNA polymerase I (Pol I) is the eukaryotic RNA polymerase that synthesizes the majority of ribosomal RNA (rRNA) for ribosome production. These include the 5.8S, 28S, and 18S rRNAs which are synthesized from a polycistronic gene in the nucleolus. The rRNAs synthesized by Pol I, the 5S rRNA, & ribosomal proteins come together to synthesize ribosomes through ribosome biogenesis. Dysregulation of Pol I activity has been established to contribute to dysregulation of ribosome biogenesis and disease state development. These conditions include but are not limited to Cincinnati …

Characterization Of Cellular And Viral Factors That Define The Stability Of The Latent Hiv-1 Reservoir, Eric Carlin

All ETDs from UAB

Human immunodeficiency virus (HIV) infection is a chronic viral illness that requires lifelong management due to the early formation of a latent viral reservoir within the patient’s CD4+ T cells. These latent infection events lay dormant within infected cells and reactivate stochastically or during periods of T cell activation presenting a major hurdle to the development of an HIV cure. As our understanding of the factors that contribute to HIV latency has evolved, we have started to appreciate latency as more than a chromatin regulation phenotype, due to the vast number of cellular factors that have been described to impact …

Transcriptional Regulation And Islet Transplantation Advantages Of Brown Adipose Tissue, Jessica D. Kepple

All ETDs from UAB

Metabolic disease encompasses various disorders, including obesity and diabetes, that negatively impact glucose and lipid homeostasis and increase the risk of co-morbidities. Adipose tissue, which regulates whole-body energy balance and acts as a specialized endocrine tissue, is negatively affected by obesity and diabetes. Brown adipose tissue (BAT) functions to dissipate excess energy as heat and therefore is an attractive target against metabolic disease. To develop more effective therapeutic strategies, BAT physiology and genetic regulatory mechanisms need to be better understood. This dissertation highlights studies seeking to illuminate novel transcriptional regulation and islet transplantation applications of BAT. We investigated the requirement …

Glycolytic Myeloid Cells Protect The Host In Tuberculosis, Hayden Thomas Pacl

All ETDs from UAB

Despite curative treatment, tuberculosis remains a leading cause of death around the world. As such, there is great interest in novel therapeutic approaches to treat this disease. One such approach aims to enhance the efficacy of host immune cells in responding to the pathogen, Mycobacterium tuberculosis—so called host-directed therapies. The metabolism of immune cells has been a central focus in the search for hostdirected therapies, and the role of glycolysis in myeloid cells, in particular, has received much attention. However, the role of glycolysis in myeloid cells in the context of tuberculosis has not yet been made clear. Here we …

Understanding The Role Of Biomechanics In Ovarian Cancer Biology, Alba Martinez Diaz

All ETDs from UAB

Mechanical forces including compression, tension, and shear stress are increasingly implicated as instigators of tumor progression. Understanding how mechanobiology drives ovarian cancer is critical to identifying potential therapies. The effect of shear stress is beginning to be studied in ovarian cancer due to the presence of ascites in the peritoneal cavity that prompts tumor cells detachment and implantation in secondary sites. Therefore, mechanical cues are present within the peritoneal cavity. A growing ovarian tumor mass also experiences compressive and tensile forces, although their participation in tumor progression still remains unclear. Additionally, there is a specific lack of incorporation of mechanobiology …

A Role For Inf-Ɣ-Inducble Transcription Factors In Antibody Secreting Cell Differentiation, Jessica N. Peel

All ETDs from UAB

Viral infections remain a major cause of morbidity and mortality. Within a viral, interferon (IFN)-ɣ-driven inflammatory microenvironment, B cells may produce antibody which is critical for rapid viral clearance and continued protection from reinfection. However, the roles of IFN-ɣ and IFN-ɣ-induced transcription factors (TFs) in driving antibody secreting cell (ASC) development from their B cell precursors are poorly understood. Herein, we identify two IFN-ɣ-inducible transcription factors (TFs), T-bet and interferon regulatory factor 1 (IRF1), that are essential for the differentiation of ASCs from IFN-g-activated B cell precursors. T-bet repressed an IFN-ɣ-inducible inflammatory gene program that was incompatible with ASC formation …

A Novel In Vitro Model To Study Immune Interactions In Glioblastoma, Hasan Alrefai

All ETDs from UAB

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Despite decades of research, GBM has a median survival of approximately 14 months, necessitating the development of novel GBM therapeutics. The drug-development process has been hindered due to the lack of high-fidelity pre-clinical models. While in-vitro models of patient-derived xenografts (PDX) present an interesting approach to modeling GBM, they typically fail to incorporate the non-cancerous cells that support tumor growth and progression. Others have attempted to address this problem by using techniques such as 3D bioprinting to incorporate astrocytes and macrophages in an extracellular matrix; however, they …

Structural Changes To Desmosomal Architecture During Assembly And Maturation, Reena R. Beggs

All ETDs from UAB

Desmosomes are macromolecular junctions important in adhesion and resisting mechanical stress in epithelial and cardiac tissue. Desmosomes have a complex architecture with transmembrane cadherins, desmogleins and desmocollins, constituting the adhesive interface and plaque proteins, including plakoglobin and desmoplakin, binding the cadherin tails and integrating with intermediate filaments. Dysregulation of desmosomes occurs in many disease states, such as cardiomyopathies, skin diseases, and various cancers. While mature desmosomes' structure is generally understood, less is known about desmosome architecture during assembly and recycling. Desmosomes are dynamic, biochemically intractable, and diffraction-limited, making them challenging to study. To overcome these obstacles, I applied the super-resolution …

Beyond Apoptosis: Insight Into The Complex Intracellular Networks That Govern Cell Fate, Hayley Neal Widden

All ETDs from UAB

The determination of cell fate is a dynamic process regulated by hundreds of proteins that converge into complex cell signaling pathways. Upon irreparable intracellular stress, a cell undergoes programmed cell death, a process known as intrinsic apoptosis. Apoptosis is regulated by the Bcl-2 family, a class of proteins that act either as pro-survival or pro-death signaling molecules. Due to the oncogenic upregulation of pro- survival Bcl-2 family proteins across human cancer cell types, a novel class of small molecule inhibitors called ‘BH3-mimetics’ have emerged as promising anti-cancer therapeutics currently under clinical investigation. Here, we highlight the crosstalk between anti-apoptotic Bcl-2 …

Biological Pathways And Processes Underlying The Cardiac Regenerative Response Post-Injury In Small And Large Mammals, Eric Yang Zhang

All ETDs from UAB

Mammalian cardiomyocytes exit the cell-cycle shortly after birth. Consequently, the adult heart is unable to properly compensate for cardiac muscle lost to injury. As such, heart failure has remained the leading cause of death in the developed world for more than three decades. In this work, we illustrate our findings in using novel in-vivo animal models to examine two regenerative phenomena observed following myocardial injury:i.) neonate cardiomyocyte proliferation in large mammals ii.) the ‘paracrine effect’ as mediated by mesenchymal stromal cells In i.) we use a large animal model of myocardial injury during the early postnatal develop-mental stage to establish …

Hyperphosphatemia Contributes To Functional Iron Deficiency And Skeletal Muscle Wasting, Brian Anthony Czaya

All ETDs from UAB

Chronic kidney disease (CKD) is a global health threat that increases risk of death, which is credible to both impaired renal function and a multitude of CKD- associated comorbidities such as systemic inflammation, anemia and skeletal muscle dys- function. A distinctive feature of CKD is the dysregulation of mineral metabolism, where excess serum levels of phosphate (hyperphosphatemia) and of fibroblast growth factor 23 (FGF23) are not only viewed as biomarkers for disease severity but also exert deleterious effects towards various CKD-associated pathologies. Elevated levels of FGF23 can lead to the activation of FGF receptor 4 (FGFR4) in cell types that …

The Role Of Pim3 Kinase In Promoting Tumorigenesis, Tumor Metastasis, And Cancer Cell Stemness In Human Hepatoblastoma, Raoud Marayati

All ETDs from UAB

Hepatoblastoma is the most common primary liver tumor in children. Despite an increasing incidence and major advances in care for other pediatric solid tumors, therapy for hepatoblastoma has remained virtually unchanged for the last 20 years, and children with metastatic or relapsed disease continue to suffer from a dismal prognosis. Treatment strategies primarily rely on cisplatin, due to its role as the most active single agent in hepatoblastoma treatment. However, chemoresistance remains a significant challenge with 54-80% of patients developing resistance to chemotherapy after 4-5 cycles of treatment. We have previously demonstrated that Proviral Integration site in Maloney murine leukemia …

Upregulation Of Somatostatin Receptor 2 In Neuroendocrine Tumors Using Histone Deacetylase Inhibitors, Rachael Elizabeth Guenter

All ETDs from UAB

Neuroendocrine cancer is complex disease of the diffuse neuroendocrine system. Neuroendocrine tumors (NETs) can arise throughout the body, including the lungs and pancreas. These tumors are phenotypically and genetically heterogeneous, making accurate diagnoses difficult with current imaging standards. New diagnostic options, coupled with a better understanding of neuroendocrine cancer etiology, is urgent and necessary to provide patients with better futures. Many NETs overexpress somatostatin receptor 2 (SSTR2) on their cellular surfaces, making patients eligible for [68Ga]-DOTATATE PET/CT imaging and SSTR2-based therapies. However, patients that lack sufficient SSTR2 overexpression cannot benefit from SSTR2-targeted imaging or therapeutic options. We found that histone …

Identifying Novel Therapeutics And Therapeutic Entry Points For The Treatment Of Duchenne Muscular Dystrophy Through Regulation Of Gene Expression, Rylie Maria Hightower

All ETDs from UAB

My graduate research has primarily focused on genetic and epigenetic modifiers of Duchenne muscular dystrophy and understanding how those modifiers can be used as novel therapeutic entry points for treatment. A vast array of promising therapeutic strategies is being explored outside the realm of directly targeting dystrophin deficiency. This is primarily due to the lack of successful clinical trials that have demonstrated the ability to benefit a significant number of DMD patients. Here, I have expanded the field’s understanding of using the regulation of gene expression as a way to target dystrophin-deficiency associated pathology through, 1) therapeutic treatment of a …