Digital Commons Network^™

Glial Fibrillary Acidic Protein And Gliosis: Is Gfap More Than A Marker?, Heather Renee Minkel

All ETDs from UAB

Alexander Disease (AxD) is a `gliopathy' caused by toxic, dominant gain-of-function mutations in the gene encoding glial fibrillary acidic protein (GFAP). Two distinct types of AxD exist. Type I AxD affected individuals develop cerebral symptoms by four years of age and generally suffer from macrocephaly, seizures, and physical and mental delays. As detection and diagnosis have improved, a larger portion, now about half of all AxD patients diagnosed, have onset >4 years and brainstem/spinal cord involvement. These type II AxD patients typically experience ataxia, palatal myoclonus, dysphagia and dysphonia. To date no study has examined a mechanistic link between the …

Altered Dna Methylation Contributes To Temporal Lobe Epilepsy And Associated Memory Deficits, Robert Ryley Parrish

All ETDs from UAB

Status epilepticus (SE) triggers molecular mechanisms that underlie the cellular and network changes that occur during the development of temporal lobe epilepsy (TLE). Additionally, gene expression alterations occur during epileptogenesis and in the epileptic brain that contribute to the persistence of the phenotype. However, the underlying epigenetic mechanisms responsible for aberrant gene expression that occur with epilepsy require further investigation. This dissertation investigates how DNA methylation in the hippocampus affects epilepsy and contributes to the memory impairments associated with the disorder. We found that DNA methylation was altered in a hippocampal subregion specific manner in the epileptic brain, displaying altered …

The Impact Of Interleukin-21 On Intestinal Inflammation During Health And Disease, Catherine Poholek

All ETDs from UAB

The intestinal environment is extremely complex due to the dynamic interactions between host cells and luminal contents. The immune cells located in the intestine are responsible for sensing and responding to intestinal pathogens as well as maintaining tolerance to non-pathogenic organisms and environmental antigens. Disruption in this delicate balance results in chronic intestinal inflammation. Particularly important to the maintenance of intestinal homeostasis are CD4 T cells and innate lymphoid cells (ILCs). These cells produce cytokines in an antigen-specific and antigen-independent manner, respectively, and have analogous subsets with similar cytokine profiles. CD4 T cells and ILCs expressing ROR gamma t (Th17 …

Molecular And Functional Interaction Of Runx2 And Sp7 For Development Of The Osteoblast Phenotype, Harunur Rashid

All ETDs from UAB

Runx2 and Sp7 transcription factors are essential for skeletogenesis. Deletion of either gene in mice results in failure of bone tissue development. However, underlying mechanisms responsible for a surprisingly similar phenotype by two distinctly unrelated proteins remain unknown. Sp7 is a Runx2 downstream target gene and is not expressed in Runx2 null mice. Thus, the Runx2 null model represents a compound phenotype of loss of both proteins. In contrast, normal levels of Runx2 mRNA are noted in Sp7 null mice. The failure of Runx2 to promote bone formation in Sp7 null mice suggests that Sp7 is required for Runx2 function …

Targeting Reactive Oxygen Species Production To Prevent Left Ventricle Remodeling In Volume Overload, Danielle Marie Yancey

All ETDs from UAB

Mechanisms of left ventricular dysfunction in cardiac volume overload (VO) are not well understood and currently, no medical therapy exists to treat this condition. Cardiac VO is marked by eccentric remodeling and contractile dysfunction ultimately resulting in cardiac failure. Oxidative stress is implicated in the pathophysiology of heart failure and recent evidence suggests mitochondrially- produced reactive oxygen species play a role in VO. To study VO, we used a rat model of aortocaval fistula (ACF). ACF results in early diastolic stress on the left ventricle (LV) and recapitulates the progressive nature of heart failure with contractile function being initially maintained …

Calreticulin Regulates Tgf-Ss Stimulated Extracellular Matrix Production, Kurt Zimmerman

All ETDs from UAB

Calreticulin (CRT) is an ER chaperone and regulator of Ca2+ signaling which is increased following ER stress and in fibrotic and vascular fibroproliferative disorders. Previously, we demonstrated that ER CRT regulates type I collagen transcript, trafficking, secretion, and processing into the extracellular matrix (ECM). These studies investigated the role of CRT in regulating ECM production through control TGF-ß dependent signaling pathways. Our studies show that CRT -/- mouse embryonic fibroblasts (MEFs), rat lung fibroblasts, and human IPF lung fibroblasts with siRNA knockdown of CRT had impaired production of type I collagen and fibronectin when stimulated with TGF-ß. Similarly, knockdown of …

Examining The Role Of G Protein-Coupled Estrogen Receptor 1 (Gper) Activation In 17beta-Estradiol-Mediated Protection In Traumatic Brain Injury, Nicole Day

All ETDs from UAB

Traumatic brain injury (TBI) affects millions of persons per year, potentially leading to permanent disability or death, and exacts a staggering financial toll. Despite the severity of this public health problem, there are no clinically proven pharmacotherapeutics available that effectively attenuate the secondary neurochemically-mediated damage that follows the initial biomechanical insult. In addition, the heterogeneous nature of TBI and complexity of secondary injury cascades suggest that a polytherapeutic approach could be a powerful strategy with which to simultaneously target more than one deleterious pathway. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of …

Alpha-Camkii-Induced Vegf Expression Is Critical For The Growth Of Human Osteosarcoma, Paul Glenn Daft

All ETDs from UAB

Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. Despite improvements in OS treatment, more specific molecular targets are needed. One target of interest is alpha-Ca2+/calmodulin-dependent protein kinase II (α-CaMKII), a ubiquitous mediator of Ca2+-linked signaling, which has been shown to regulate tumor cell proliferation. Here, we show that α-CaMKII is highly expressed in primary OS tissue, and α-CaMKII deletion in human OS cell lines significantly reduces tumor burden in vivo. This inhibition of α-CaMKII results in decreased vascular endothelial growth factor (VEGF) protein secretion. Highly aggressive OS cells express VEGF receptor …

Comparisons Between The Nod And Nor Mouse: Insight Into Diabetes Pathogenesis And Protection, Joseph Guy Daft

All ETDs from UAB

Type 1 Diabetes (T1D) is defined as the selective immune destruction of insulin producing beta cells within the islet. A new emphasis has been put on the role of the gastrointestinal (GI) tract in T1D; however, there is much more to learn about this relationship. Distinct differences have been observed in the intestinal permeability, barrier function, commensal microbiota, and mucosal innate and adaptive immunity of patients and animals with T1D, when compared to healthy controls. The non-obese diabetic (NOD) mouse and the BioBreeding diabetes prone (BBdp) rat are commonly used to models to study T1D in humans. Most murine studies …

The Multifaceted Role Of Neutrophils In Hiv-1-Infection, Nathan Bowers

All ETDs from UAB

In recent years, a new appreciation of the role of neutrophils in regulating the immune system has emerged. Neutrophils are the most abundant leukocyte population and are traditionally recognized as essential effector cells of the innate immune system in the host defense against invading organisms. Neutrophils play a critical role in controlling bacterial and fungal infections by multiple mechanisms including phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs). Neutrophils have been shown to play important roles in viral pathogenesis, a knowledge gap exists in our understanding of the function of neutrophils in individuals infected with human immunodeficiency virus-1 (HIV-1). …

Sialic Acid: A Signal For Pneumococcal Egress From The Nasal Mucosa Into The Central Nervous System, Brandon L. Hatcher

All ETDs from UAB

Streptococcus pneumoniae (pneumococcus) is one of the leading causes of bacterial meningitis world-wide. The classic paradigm in the establishment of bacterial meningitis is that in the absence of physical trauma, infection in the peripheral blood is needed to cause invasion of the central nervous system (CNS). Our previous studies have shown that pneumococci, a frequent colonizer of the nasopharynx, can cause bacterial meningitis through a nonhematogenous route by which bacteria appear to travel along the olfactory nerves, through the cribriform plate to the olfactory bulbs and into the rest of the CNS. However, with the frequency of nasopharyngeal colonization and …

The Role Of Gene Fragmentation And Loss In Poxvirus Evolution, Eneida Hatcher

All ETDs from UAB

temperatures were near pivotal. The second chapter addresses the effects of fluctuating

Proteomic Analysis Of Rosenthal Fibers And The Development Of Software For Proteomics, Michael Raymond Heaven

All ETDs from UAB

The first aim of my thesis was to identify the protein composition of the protein aggregates, called Rosenthal fibers, which are the defining feature of Alexander disease (AxD). AxD is a rare neurodegenerative disease caused by mutations in the astrocyte specific protein, glial fibrillary acidic protein (GFAP). GFAP is a type III intermediate filament protein that is overexpressed in AxD. A guiding hypothesis of this project was that sequestration of vital cell proteins in the aggregates contributed to disease. The results of my research do not support this hypothesis, but do provide an in depth characterization of the protein composition …

Role Of Immunoregulatory Cytokines Il-12 And Il-23 In Skin Cancer, Tahseen H. Nasti

All ETDs from UAB

The incidence of new cases of skin cancer, which includes non-melanoma epithelial tumors and melanoma, has increased dramatically over the last few decades. Approximately 75% of all skin cancer-related deaths is due to melanoma, which is one of the most aggressive and difficult cancers to treat. The initiating events and mechanisms that influence melanoma development are not fully known, due in part to a paucity of animal models amenable to identifying new oncogenic mutations, and investigating mechanisms of immunosurveillance. Transgenic mouse models often harbor an activating mutation in a known oncogene in all somatic cells, and its widespread expression from …

Synaptic Organization Of Noradrenergic And Opioid Circuitry In The Basolateral Amygdala: Anatomical Correlates Of Memory Consolidation, Jingyi Zhang

Theses and Dissertations

The studies comprising this dissertation were designed to investigate the synaptic organization of norepinephrine and opioid system in the anterior subdivision of the basolateral nucleus of amygdala (BLa) in rat. Light and electron microscopy were combined with immunohistochemistry to determine the synaptic incidence and postsynaptic targets of noradrenergic axon terminals, to localize mu opioid receptor at the ultrastructural level and to determine whether there is convergence of norepinephrine inputs and enkephalin inputs in the BLa. It was determined that about half of the norepinephrine inputs formed synapses in the BLa and the main postsynaptic targets were small caliber CAMK+ dendritic …

Peripubertal Binge Ethanol, Age And Sex Modulate Microrna Expression In The Ventral And Dorsal Hippocampus Of The Adolescent Rat, Sarah Arianne Prins

Dissertations

Adolescent binge ethanol (EtOH) abuse induces long-term changes in gene expression, resulting in an increased risk for the development of adult mood disorders. microRNAs (microRNAs) are small, noncoding RNAs that regulate gene expression by translational repression. microRNA altered in response to EtOH and puberty in the developing brain. The biogenesis of mature 22-24 nucleotide (nt), single-stranded microRNAs involves Drosha and Dicer enzymatic processing of microRNA precursors. A mature microRNA imperfectly base pairs with messenger RNA (mRNA) target genes,which leads to mRNA cleavage or translational repression. Our lab has found that repeated binge EtOH exposure alters gene expression in the hypothalamus …

A Study Of Functional Recovery And Axonal Plasticity Following Tbi And Anti-Nogo-A Immunotherapy, Jennifer Crystal Biesiadecki

Master's Theses

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality globally and often results in long term disability. Unfortunately, the success of rehabilitation techniques as therapy for TBI is limited, which may be due to the growth restrictive environment of the adult central nervous system (CNS). This environment is thought to result from glial scars, lack of neurotrophic factors, and the presence of an array of growth-inhibitory molecules. One such growth-inhibitory molecule is the protein Nogo-A. Our laboratory has shown that neutralization of Nogo-A with anti-Nogo-A immunotherapy after ischemic stroke results in improvement in functional recovery in the …

An Analysis Of Fatty Acid Metabolism’S Role In The Development Of Acute Functional Tolerance To Ethanol In Caenorhabditis Elegans, Richard Raabe

Theses and Dissertations

An individual’s naïve level of response (LR) to ethanol is predictive of their lifetime likelihood to abuse alcohol. LR is heavily genetically influenced, suggesting that the genes responsible for LR may also be central to the development of abuse disorders. Our laboratory uses the model organism C. elegans to investigate the genetic influences on responses to acute ethanol exposure. We recently found that changes in TAG levels can alter LR. From this result we investigated the role of long-chain polyunsaturated fatty acids (LC-PUFAs) as well enzymes involved in lipid modifications of proteins. We found that LC-PUFAs are necessary for acute …

Characterization Of Complement Evasion Of The Periopathogen, Treponema Denticola, Daniel Patrick Miller

Theses and Dissertations

Periodontitis is a polymicrobially-induced, chronic inflammatory disease of the tissues that support and surround the tooth. While greater than 500 organisms are found in dental plaque, Treponema denticola is one of only a few species associated with disease. It has been hypothesized that oral bacteria disrupt host homeostasis through manipulation of the innate immune system. In this study, we examine the impact of binding and subsequent cleavage of factor H, a complement regulator, by T. denticola in the evasion and subversion of complement. The molecular interaction between the sole FH-binding protein, FhbB, and FH was detailed by x-ray crystallography, site-directed …

Novel Therapeutic Strategies For Pancreatic Cancer, Bridget A. Quinn

Theses and Dissertations

Pancreatic cancer is a devastating disease that leaves patients with a very poor prognosis and few therapeutic options. Many of the treatment options available are the same that have been used for almost 2 decades. There is a dire need for both novel treatments for this disease as well as novel strategies of treatment. This body of work will introduce and provide evidence in support of a novel combination therapy for pancreatic cancer treatment, a novel strategy of modifying currently used chemotherapeutics for pancreatic cancer therapy, and a novel transgenic preclinical mouse model of pancreatic cancer. Sabutoclax, an antagonist of …

Faculty Publications 2013, Lsu Health Sciences Center New Orleans

Historical Faculty Publications

This Faculty bibliography contains 806 publications.

Anxiety Symptoms, Cerebral Amyloid Burden And Memory Decline In Healthy Older Adults Without Dementia: 3-Year Prospective Cohort Study, Robert H. Pietrzak, J C. Scott, Alexander Neumeister, Yen Ying Lim, David Ames, Kathyrn A. Ellis, Kara Harrington, Nicola T. Lautenschlager, Cassandra Szoeke, Ralph Martins, Colin L. Masters, Victor L. Villemagne, Christopher C. Rowe, Paul Maruff

Research outputs 2014 to 2021

Although beta-amyloid, anxiety and depression have been linked cross-sectionally to reduced memory function in healthy older adults without dementia, prospective data evaluating these associations are lacking. Using data from an observational cohort study of 178 healthy older adults without dementia followed for 3 years, we found that anxiety symptoms significantly moderated the relationship between beta-amyloid level and decline in verbal (Cohen's d = 0.65) and episodic (Cohen's d = 0.38) memory. Anxiety symptoms were additionally linked to greater decline in executive function, irrespective of beta-amyloid and other risk factors. These findings suggest that interventions to mitigate anxiety symptoms may help …

The Reliability Of An Adolescent Dietary Pattern Identified Using Reduced-Rank Regression: Comparison Of A Ffq And 3 D Food Record, Geeta Appannah, Gerda K. Pot, Therese A. O'Sullivan, Wendy H. Oddy, Susan A. Jebb, Gina L. Ambrosini

Research outputs 2014 to 2021

Despite the increasing use of dietary patterns (DP) to study diet and health outcomes, relatively few studies have examined the reliability of DP using different dietary assessment methods. Reduced-rank regression (RRR) is an emerging statistical method that incorporates a priori information to characterise DP related to specific outcomes of interest. The aim of the present study was to compare DP identified using the RRR method in a FFQ with those in a 3 d food record (FR). Participants were 783 adolescents from the Western Australian Pregnancy (Raine) Cohort Study who completed both a FFQ and FR at 14 years of …

Biomarkers Of Alzheimer's Disease Risk In Peripheral Tissues; Focus On Buccal Cells, Maxime François, Wayne Leifert, Ralph Martins, Philip Thomas, Michael Fenech

Research outputs 2014 to 2021

Alzheimer's disease (AD) is a progressive degenerative disorder of the brain and is the most common form of dementia. To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. Therefore, if population screening of individuals is to be performed, more suitable, easily accessible tissues would need to be used for a diagnostic test that would identify those who exhibit cellular pathology indicative of mild cognitive impairment (MCI) and AD risk so that they can be prioritized for primary prevention. This need …

Impact Of Nutrition On Cognition And Its Association With Blood And Brain Alzheimer Disease Related Biomarkers, Samantha Gardener

Theses: Doctorates and Masters

Alzheimer’s disease (AD), the most common form of senile dementia, currently affects over 35 million people worldwide. While there is no cure or effective treatment, early intervention programs hold considerable promise. Following particular dietary patterns represents one potential intervention strategy accessible to all.

Results from previous studies investigating the association of diet, cognition and biomarkers of AD are inconsistent: Positive results have been reported (1-7), whilst others have shown no associations. Prior to this thesis, no study has assessed the relationship of four dietary patterns to cognition, blood-based and neuroimaging biomarkers of AD in a large highly-characterised ageing cohort. Participants …

The Impact Of Implementing A Sudden Infant Death Syndrome Education Package In Jordan, Shereen Hamadneh

Theses: Doctorates and Masters

Background: Sudden Infant Death Syndrome (SIDS) is a problem worldwide. In North Jordan, SIDS rate was high as 1.32 per 1,000 live births and contributed 6% to the infant mortality rate (Bataineh, Shawagfeh, & Twalbeh, 2008). However, SIDS risk factors are preventable and can be reduced by improving knowledge and changing relevant behaviours of parents and healthcare providers (American Academy of Pediatrics, 2013; American SIDS Institute, 2011; Bataineh, Hussein Shawagfeh, & Twalbeh, 2008; Bredemeyer, 2004; Grazel, Phalen, & Polomano, 2010b; Moon, Oden, & Grady, 2004; NICHD, 2010). Still educating Jordanians about SIDS has not been a national health policy priority. …

Synthetic Triterpenoids Can Protect Against Toxicity Without Reducing The Efficacy Of Treatment With Carboplatin And Paclitaxel In Experimental Lung Cancer, Karen T. Liby

Dartmouth Scholarship

Synthetic oleanane triterpenoids are multifunctional drugs being developed for the prevention and treatment of a variety of chronic diseases driven by inflammation and oxidative stress. Low nanomolar concentrations of triterpenoids inhibit the induction of inflammatory cytokines, and these drugs are potent activators of the Nrf2 cytoprotective pathway. In contrast, low micromolar concentrations of triterpenoids increased the production of ROS and induced apoptosis in a dose-dependent manner in malignant MCF10 CA1a breast cancer cells. Because cancer cells respond differently to ROS than normal cells, it should be possible to exploit these differences therapeutically. In an experimental model of lung cancer, the …

Novel Roles For Actin In Mitochondrial Fission, Anna L. Hatch, Pinar S. Gurel, Henry N. Higgs

Dartmouth Scholarship

Mitochondrial dynamics, including fusion, fission and translocation, are crucial to cellular homeostasis, with roles in cellular polarity, stress response and apoptosis. Mitochondrial fission has received particular attention, owing to links with several neurodegenerative diseases. A central player in fission is the cytoplasmic dynamin-related GTPase Drp1, which oligomerizes at the fission site and hydrolyzes GTP to drive membrane ingression. Drp1 recruitment to the outer mitochondrial membrane (OMM) is a key regulatory event, which appears to require a pre-constriction step in which the endoplasmic reticulum (ER) and mitochondrion interact extensively, a process termed ERMD (ER-associated mitochondrial division). It is unclear how ER-mitochondrial …

Altered Cytological Parameters In Buccal Cells From Individuals With Mild Cognitive Impairment And Alzheimer's Disease, Maxime François, Wayne Leifert, Jane Hecker, Jeffrey Faunt, Ralph Martins, Philip Thomas, Michael Fenech

Research outputs 2014 to 2021

Previous studies have shown that mild cognitive impairment (MCI) may be reflective of the early stages of more pronounced neurodegenerative disorders such as Alzheimer's disease (AD). There is a need for a minimally invasive and inexpensive diagnostic to identify those who exhibit cellular pathology indicative of MCI and AD risk so that they can be prioritized for primary preventative measures. The hypothesis was that a minimally invasive approach using cytological markers in isolated buccal mucosa cells can be used to identify individuals of both MCI and AD. An automated buccal cell assay was developed using laser scanning cytometry (LSC) to …

The Effects Of Nesting Environment On Neonatal Hypoxic-Ischemic Injury, Laura Grace Rollins

Graduate Masters Theses

Term neonates with hypoxic-ischemic (HI) injury are at risk for devastating neurological sequelae. The objective of this study is to determine if altering the early environment for maternal care-taking impacts the immediate and long-term sequelae of HI offspring. The Rice-Vannucci model was used to induce HI in postnatal day (PND) 7 Long-Evans pups. Litters were assigned to a closed nest (CN) or normal standard housing (SH) condition. Neurobehavioral development, cognitive ability, and stress response were assessed to establish any benefits of the CN condition. Finally, postmortem brain tissue was analyzed for morphometric markers of injury.