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Articles 121 - 150 of 1029
Full-Text Articles in Medical Sciences
The Identification And Phenotypic Characterization Of Circulating Flagellin Antigen-Specific Cd4+ T Cells In Crohn's Disease Patients, Nadine N. Morgan
The Identification And Phenotypic Characterization Of Circulating Flagellin Antigen-Specific Cd4+ T Cells In Crohn's Disease Patients, Nadine N. Morgan
All ETDs from UAB
The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Crohn’s disease (CD) and Ulcerative colitis (UC), the two main subtypes of IBD, are chronic intestinal conditions driven by CD4+ T-cell inflammatory responses to commensal antigen. Both conditions are incurable, and medical treatments involve drugs that require long-term usage but have limited efficacy and significant side effects. To develop therapies targeting the antigen-reactive T cells involved in sustaining these conditions, we must first gain knowledge concerning the microbial antigen-reactive T cell phenotypes and functionality in health and disease. To investigate the phenotypic and functional characteristics of the flagellin-reactive T cell …
Disease And Diet-Induced Disruption Of Effector T Cell Homeostasis, Patrick Axel Molina
Disease And Diet-Induced Disruption Of Effector T Cell Homeostasis, Patrick Axel Molina
All ETDs from UAB
Homeostatic departure is a central feature across all diseases and disease processes. Currently, the average individual in the US consumes an inordinate quantity of salt. However, it is unclear if only individuals that have proven blood pressure elevation with an acute load of salt should be wary. Here we demonstrate, alongside a growing body of science, that the canonical definition of salt-sensitivity is insufficient. We show that salt-resistant mice demonstrate salt-sensitivity in non-blood pressure focused phenomena, such as the acute activation of CD4+ T cells to mobilize and induce a defective effector cytokine program with high salt. We demonstrate that …
The Roles Of Repressive And Activating Epigenetic Factors In Vertebrates Neural And Neural Crest Development, Saeid Mohammad Parast
The Roles Of Repressive And Activating Epigenetic Factors In Vertebrates Neural And Neural Crest Development, Saeid Mohammad Parast
All ETDs from UAB
The vertebrate nervous system comes from specific regions of the ectoderm that comprises of the neural plate and the neural crest. Although genetic mechanisms governing vertebrate neural development have been investigated in depth, there is a knowledge gap regarding the roles of epigenetic mechanisms in this process. As epigenetic modulators, the COMPASS (also known as SET1/MLL complex) and HP1 proteins are responsible for regulating chromatin accessibility to transcription factors. COMPASS is responsible for deposition of activating histone H3K4 methylation marks at promoters and enhancers and thus creates open chromatin domains. The critical structural and regulatory subunits of COMPASS, Dpy30 and …
Regulation Of Stromal Cells Through Inflammatory Signalling, Victoria Matkins
Regulation Of Stromal Cells Through Inflammatory Signalling, Victoria Matkins
All ETDs from UAB
The bone marrow is a complex organization of hematopoietic and nonhematopoietic cells that form niches to maintain systemic homeostasis during stress and disease. Stromal cells are non-hematopoietic cells first proposed in 1978 in the bone marrow to be essential for hematopoietic stem cells (HSC). Since then, mesenchymal stromal cells (MSC) have been shown to be critical for the HSC self-renewal, retention, and differentiation through chemokines, cytokines, and adhesion molecules. However, like HSCs, MSCs are multipotent progenitors that differentiate into osteoblasts, adipocytes, and chondrocytes to from tissues of the skeletal, endocrine, and connective systems. These multipotent progenitors are tightly regulated in …
Primary Cilia Regulate Inflammation And Macrophage Accumulation During Injury And Cyst Formation In Mouse Pkd Models, Zhang Li
All ETDs from UAB
Polycystic kidney disease (PKD) is one of the most common inherited renal disorders. The most common form, autosomal dominant polycystic kidney disease (ADPKD), affects more than 13 million people around the world, and over 50% of them will develop end-stage renal disease (ESRD). Although ADPKD genetically is caused by mutations of PKD1 or PKD2 genes, there is increasing evidence showing that non-genetic factors such as renal injury and inflammation play important roles in cyst severity and progression in PKD. Macrophages are cells of the innate immune system known to be involved in kidney injury and repair. Data from our lab …
Roles Of Chemokine Receptors In T Cell Accmulation In Omental Tumors, Mingyong Liu
Roles Of Chemokine Receptors In T Cell Accmulation In Omental Tumors, Mingyong Liu
All ETDs from UAB
The omentum is an adipose tissue in the peritoneal cavity that contains immune aggregates termed milky spots. Functionally similar to conventional lymphoid tissues, these specialized leukocyte clusters harbor effector and suppressor cells, mount immune responses to antigens, and sustain peritoneal homeostasis. However, the pre-existing leukocytes fail to protect the tissue from tumor colonization. In fact, the omentum is frequently involved in peritoneal metastasis, during which the balance between effector and suppressor immune cells is compromised with the latter gaining dominance. Regulatory T cells (Tregs) represent a major immunosuppressive population in the omentum and rapidly accumulate after tumor implantation. The increased …
Elucidating Pgc-1Α And Errγ Gene Regulation In Neurons, Kathlene Lanphear Joyce
Elucidating Pgc-1Α And Errγ Gene Regulation In Neurons, Kathlene Lanphear Joyce
All ETDs from UAB
Neuronal energy production is critical to the function of the entire central nervous system. Without enough ATP, neurons are not able to maintain their synaptic structure or activity, leading to a circuit-wide dysregulation, affecting movement and memory. The main process for ATP production in neurons is oxidative phosphorylation, which is supported by several proteins encoded by nuclear DNA. Transcription of nuclear DNA is regulated by DNA-binding transcription factors and co-activators which recruit other members of the transcription initiation complex to induce gene expression. While important basally, during neurodegenerative diseases such as Parkinson’s Disease, the transcription of these genes is altered …
Driving Anger And Aggression In Persons With And Without Adhd, Maria T. Lechtreck
Driving Anger And Aggression In Persons With And Without Adhd, Maria T. Lechtreck
All ETDs from UAB
Driving a motor vehicle is both a privilege and one of the primary activities of daily living for most persons in the U.S. and many persons abroad; however, motor vehicle collisions (MVCs) bring great costs both to individuals and society. Driver behavior is the critical factor in an estimated 94% of MVCs and aggressive driving is the cause of two-thirds of U.S. traffic fatalities. Certain populations are at an increased risk for MVCs including persons who are young (ages 15-24), persons who have developmental disabilities such as Attention-Deficit/Hyperactivity Disorder (ADHD), and persons who have a high propensity for driving-related anger. …
Determining The Impact Of Immune Dysregulation On Cd4 T Cell Responses To Hiv-1 And Sars-Cov-2, Jacob K. Files
Determining The Impact Of Immune Dysregulation On Cd4 T Cell Responses To Hiv-1 And Sars-Cov-2, Jacob K. Files
All ETDs from UAB
CD4+ T cells, often referred to as helper T cells, play a crucial role in the formation of antiviral immune responses following infection and vaccination. However, this can be disrupted by various forms of immune dysregulation. Many groups have described how HIV-1 adaptation and immune escape can lead to dysregulated HIV-specific immune responses. Our lab has previously shown that predicted HLA-II associated HIV-1 adaptation leads to dysregulated, poorly immunogenic CD4+ T cell responses in HIV-1 infection. Here, we focus on the impact of this HLA-II associated viral adaptation in the setting of HIV-1 vaccination. We show that HLA-II associated, vaccine-matched …
The Role Of Protein Translation And Degradation In Aging And Alzheimer Disease Pathogenesis, Harper S. Kim
The Role Of Protein Translation And Degradation In Aging And Alzheimer Disease Pathogenesis, Harper S. Kim
All ETDs from UAB
Protein translation (PT) is an essential cellular process playing crucial roles in growth and development. PT precipitously declines with age in multiple animal species, including humans. It has been implicitly assumed that elevated PT at young ages is beneficial to health while PT ends up dropping as a passive byproduct of aging. However, whether this holds true and how dynamic fluctuations in PT over time impact aging remain unknown. In Drosophila, we show that a transient PT spike in early-adulthood drives aging by triggering dysfunction in protein homeostasis (proteostasis) at old ages. We propose the early-adulthood spike in PT to …
Characterizing The Role Of Tissue-Specific Retinol Dehydrogenases, Kelli Rae Goggans
Characterizing The Role Of Tissue-Specific Retinol Dehydrogenases, Kelli Rae Goggans
All ETDs from UAB
The bioactive form of vitamin A, retinoic acid is essential for development, cellular differentiation, epigenetic modifications, the immune system, and a variety of other processes due to its ability to regulate over 500 genes through activation of nuclear receptors. While many studies have focused on characterizing the biosynthesis and signaling of retinoic acid in embryogenesis, few have focused on adult tissues. Recent research has identified a novel retinol dehydrogenase, retinol dehydrogenase epidermal 2 (RDHE2), and shown RDHE2 is a potent, physiologically relevant retinol dehydrogenase in Xenopus. The work in this dissertation characterizes RDHE2 in mammalian models. We identify a paralog …
Understanding The Protumorigenic Functions Of St6gal1 In Glioblastoma Stemness And Metabolism, Sajina Gc
Understanding The Protumorigenic Functions Of St6gal1 In Glioblastoma Stemness And Metabolism, Sajina Gc
All ETDs from UAB
Glioblastoma (GBM) is a rare but deadly cancer with median survival of just 15 months despite of aggressive treatment. Advancement in novel treatment modalities is hindered by its heterogeneous nature, which includes subsets of neural stem cell-like brain tumor initiating cells (BTICs) that are highly tumorigenic and therapy-resistant. bgalactoside a-2,6-sialyltransferase 1 (ST6Gal1) is elevated in most tumors including in normal and neoplastic stem cells. ST6Gal1 imparts oncogenic phenotypes such as invasion, apoptosis evasion, therapy resistance, TIC maintenance among others via sialylation of critical receptors like, Fas, TNFR1, EGFR and more. Yet ST6Gal1 led regulation of BTIC specific cell surface proteins …
Transcriptional Regulation Of Metabolism And Synaptic Function In Neurons, Stephanie N. Fox
Transcriptional Regulation Of Metabolism And Synaptic Function In Neurons, Stephanie N. Fox
All ETDs from UAB
Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are all unifying features of neurodegenerative disorders, including Parkinson’s Disease. Parkinson’s Disease is a debilitating movement disorder with no known cure, leading sci-entists to explore the underlying etiological contributors to neuronal dysfunction and loss to devise strategies for neuroprotection. Estrogen-related receptor gamma (ERRγ) is a member of a family of transcription factors which regulate the expression of mitochondrial genes. To determine whether ERRγ modulation can provide insight into transcriptional and mitochondrial dysfunction with neurodegeneration, the experiments in this thesis project determined 1) the importance of transcription of mitochondrial genes in disease as regu-lated …
Epigenetic Regulation Of Gene Expression In Temporal Lobe Epilepsy, Rebecca Mary Hauser
Epigenetic Regulation Of Gene Expression In Temporal Lobe Epilepsy, Rebecca Mary Hauser
All ETDs from UAB
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by seizures originating from the temporal lobe of the brain. A frequent seizure focus in TLE is the hippocampus, a structure located within the temporal lobe crucial for its role in memory formation. Seizures are an excess of synchronous excitation in the brain caused by a surplus of excitatory neurotransmission and a lack of sufficient inhibitory transmission. Coordinating the process of neuronal transmission is differential expression of genes likely resulting in an increase or decrease in proteins responsible for neural signaling such as neurotransmitters, ion …
Il-2-Mediated Stat3 Activation Controls Effector T Regulatory Cell Development, Emma C. Dean
Il-2-Mediated Stat3 Activation Controls Effector T Regulatory Cell Development, Emma C. Dean
All ETDs from UAB
Heterogeneity in phenotype and function of Treg cells is becoming increasingly appreciated, especially in the context of creating potent Treg cell–based therapeutics in the treatment of inflammatory bowel disease. One of the barriers to developing such therapeutics is the limited understanding of the signals that play a role in the development of Treg cell subsets. Here, we found STAT3 signaling to be enriched in induced IL-10 competent Treg (iTreg) cells in the colon. Through the development of a new in vitro system, we found that STAT3 was required for proper development of IL-10 competent iTreg cells and that IL-2 regulated …
Integrated Phenotypic And Molecular Expression Circuits In End-Stage Osteoarthritis, Devin J. Drummer
Integrated Phenotypic And Molecular Expression Circuits In End-Stage Osteoarthritis, Devin J. Drummer
All ETDs from UAB
Osteoarthritis (OA) is a debilitating, inflammatory, joint degeneration disorder, and is the most common form of arthritis. Individuals reaching end-stage OA often pursue elective total hip/knee arthroplasty (THA/TKA) to relieve pain and improve mobility and quality of life. However, approximately one third of THA/TKA patients suffer long-term mobility impairments following surgery, likely in part due to an inability to repair the damaged muscle surrounding the diseased joint. Mechanisms driving this impaired recovery remain poorly understood, therefore it is prudent to interrogate the molecular signatures in skeletal muscle at the time of surgery to provide candidate markers that may improve upon …
Molecular And Cellular Mechanisms Of Resistance Training-Induced Skeletal Muscle Hypertrophic Response Heterogeneity In Older Adults, Margaret Bell
Molecular And Cellular Mechanisms Of Resistance Training-Induced Skeletal Muscle Hypertrophic Response Heterogeneity In Older Adults, Margaret Bell
All ETDs from UAB
Sarcopenia is a decrease in skeletal muscle (SKM) mass occurring with age. This disease is natural, so it is important to increase SKM mass to counteract. This need is seen in diseases leading to muscle atrophy (i.e., insulin resistance and diabetes). The most efficient way to promote SKM hypertrophy is resistance exercise training (RT), however there is high response heterogeneity. To investigate SKM heterogeneity and maximizing SKM hypertrophy, we conducted a double-blind two-site placebo controlled clinical trial: “Metformin to Augment Strength Training Effective Response in Seniors (MASTERS)”. Here participants > 65 years underwent RT for 14 weeks. Measurements of SKM mass …
The Role Of Mitochondrial Genetic Background In Cellular Function, Response To Cell Stress And Disease Susceptability, Jamelle A. Brown
The Role Of Mitochondrial Genetic Background In Cellular Function, Response To Cell Stress And Disease Susceptability, Jamelle A. Brown
All ETDs from UAB
There is a differential susceptibility associated with several diseases including cardiovascular disease (CVD) and hypertension, with Blacks being more likely to develop these conditions. Blacks are also more likely to die from these diseases. To explain the genetic etiology underlying CVD pathogenesis, the primary focus has been on nuclear genetics-environmental interactions, whereas the contribution of mitochondrial genetics is less explored. Therefore, we sought to determine whether differences exist in cellular function and response to cell stress in healthy and diseased individuals with distinct mitochondrial genetic backgrounds. To determine this, we sought first to develop a technique to detect and quantify …
Epigenetic Regulation By O-Glcnac Alters Anti-Fibrotic Gene Expression In Ipf Fibroblasts, Qiuming Wu
Epigenetic Regulation By O-Glcnac Alters Anti-Fibrotic Gene Expression In Ipf Fibroblasts, Qiuming Wu
All ETDs from UAB
Idiopathic pulmonary fibrosis (IPF) is an age-related chronic disease with a me-dian survival period of 3-4 years [1]. Although FDA has approved two drugs that may slow the disease process, there is no effective treatment [2]. IPF is characterized by the excessive deposition of collagen, which leads to deformation of alveolar structure, loss of lung function, and ultimately death [3]. Anti-fibrotic genes such as cyclooxygenase-2 (COX-2) and Heme Oxygenase 1 (HMOX-1) are usually suppressed in the pathogenesis of IPF [4-6], while the mechanisms responsible for the repression of anti-fibrotic genes in IPF are incompletely understood. More evidence has shown that …
The Role Of Complement C3 In Iga Nephropathy, Sarah Elizabeth Coffee
The Role Of Complement C3 In Iga Nephropathy, Sarah Elizabeth Coffee
All ETDs from UAB
IgA nephropathy is an autoimmune disease characterized by glomerular IgA1- containing immunodeposits. These immunodeposits are enriched for aberrantly glycosylated IgA1 bound by IgG autoantibodies and contain complement component C3. Current research suggests a multi-hit disease pathogenesis: IgAN patients have elevated serum levels of IgA1 missing galactose in some hinge region O-glycans; this galactosedeficient IgA1 is recognized by IgG autoantibodies resulting in formation of circulating immune complexes; some of these complexes deposit in the glomeruli and induce kidney injury. As there is no disease-specific treatment, many patients progress to kidney failure. In this master’s thesis I sought to assess whether C3 …
A Gastrointestinal-Specific Antibiotic As An Experimental Treatment For Anxio-Depressive Disorders, Yuang-Tai Huang
A Gastrointestinal-Specific Antibiotic As An Experimental Treatment For Anxio-Depressive Disorders, Yuang-Tai Huang
All ETDs from UAB
Chronic stress is a predisposing factor for various disease states, including neuropsychiatric disorders, such as depression and anxiety [1]. Stress-related disorders have complicated multifactorial etiologies [2]. Advances in psychotherapeutic and psychotropic treatments have occurred, but anxiety and depressive disorders are still prevalent and remain a burden to our societies [3]. More than 30% of major depressive disorder patients fail to remission despite an FDAapproved medication [4]. Meanwhile, the contribution of microbiota-gut-brain axis signaling in both etiologies and treatment of stress-related disorders is increasingly being recognized [5]. More evidence has shown that the gut microbiota has the potential to alter the …
Study Of Microrna-23a Cluster In Bone Formation, Revati Suryawanshi
Study Of Microrna-23a Cluster In Bone Formation, Revati Suryawanshi
All ETDs from UAB
The differentiation of mesenchymal stem cells to pre-osteoblasts, lies upon various transcription factors and physiological signaling, but is also governed by the micro-RNA-23a cluster. The miR-23a cluster has miR-23a, miR-27a and miR-24-2 transcribed from a single promoter as a sole RNA primary transcript. Its effects have been observed in embryonic stem cells, mesenchymal stem cells (MSCs), and in cancer (1-2). It regulates the lineage commitment of MSCs. (3). With respect to bone formation, miR-23a cluster is involved MSCs commitment to and osteoblast maturation (4). Here, through in vivo and in vitro experiments, we report that knock down of microRNA-23a cluster …
Grainyhead-Like 2 (Grhl2) Has Anti-Oncogenic Potential In Glioblastoma, Rachel M. Carnes
Grainyhead-Like 2 (Grhl2) Has Anti-Oncogenic Potential In Glioblastoma, Rachel M. Carnes
All ETDs from UAB
Grainyhead-like 2 (GRHL2) is a complex transcription factor associated with roles in both development and cancer. In development, GRHL2 suppresses a series of genes associated with the mesenchymal phenotype, while actively promoting the expression of genes associated with the epithelial phenotype. Due to this GRHL2 is considered a main gatekeeper of the epithelial to mesenchymal transition (EMT), playing a crucial role in epithelial morphogenesis and neural tube closure. These basic traits for GRHL2 have also been found to be similar in cancer. GRHL2 has multi-faceted functions in cancer, in which it can be considered either an oncogene or a tumor …
The Role Of Dock3 In Normal Skeletal Muscle Function And Metabolism, Adrienne Samani
The Role Of Dock3 In Normal Skeletal Muscle Function And Metabolism, Adrienne Samani
All ETDs from UAB
DOCK (dedicator of cytokinesis) are proteins of an 11-member family of typical guanine exchange factors (GEFs) expressed almost exclusively in the brain and spinal cord. Human pathogenic DOCK3 variants have been identified to cause debilitating neuromuscular phenotypes such as muscle hypotonia, ataxia, and intellectual disability. Our lab identified DOCK3 as being strongly upregulated in Duchene muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patient and mouse skeletal muscles. Global Dock3 KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. Similarly, DOCK3 KO mice appeared to have poor muscle architecture, locomotive activity, reduced myogenic fusion, impaired …
Alterations In Synaptic Structure And Tau Phosphorylation In Alheimer's Disease, Courtney K. Walker
Alterations In Synaptic Structure And Tau Phosphorylation In Alheimer's Disease, Courtney K. Walker
All ETDs from UAB
Alzheimer’s disease (AD) is the most common cause of dementia in individuals over the age of 65. Of the two hallmark pathologies of AD, tau neurofibrillary tangles (NFTs) correlate more strongly with cognitive decline than do Aβ plaques. NFTs form in the entorhinal cortex (EC) and appear in anatomically connected regions over time as disease progresses. This tau spreading may occur via synaptic connections. Most excitatory synapses occur on dendritic spines, which house the postsynaptic machinery. Spines are actin-rich, plastic structures that change their size and shape in response to synaptic activity in a process that is dependent on actin …
The Requirement Of Transcriptional Lim Complex Co-Regulators For Pancreatic Endocrine Cell Development And Function, Eliana Davi Toren
The Requirement Of Transcriptional Lim Complex Co-Regulators For Pancreatic Endocrine Cell Development And Function, Eliana Davi Toren
All ETDs from UAB
The prevalence and tremendous impact of diabetes mellitus has made glucose regulation of the insulin-producing -cell and surrounding pancreatic islet of Langerhans a center of public and research interests alike. A comprehensive understanding of these hormone-producing cells begins with their developmental origins. What are the genetic cues and participants in the tightly orchestrated process of their formation? Investigating the earliest determinants of islet-cell fate not only allows us to deeply understand mature - and islet-cell function, but also produces a data-driven template for how these cells can be reproduced in future stem-cell based diabetes therapies. LIM transcriptional complexes are indispensable …
Effects Of Exercise On Cerebral Oxygen Extraction Fraction, Hippocampal Subfields, And Cognition In Older Women, Amani M. Norling
Effects Of Exercise On Cerebral Oxygen Extraction Fraction, Hippocampal Subfields, And Cognition In Older Women, Amani M. Norling
All ETDs from UAB
Cardiorespiratory fitness (CRF) is associated with enhanced cognitive functions in aging. The relationship between fitness and brain function is supported by evidence of improvements or maintenance of gray matter volume, and cerebral blood flow (CBF). Research focused on interactions between CRF and changes in cerebral structure and function have not identified the underlying mechanisms of exercise-induced improvements, and none included the effects of CRF on cerebral oxygen extraction fraction (OEF), which is a measure of the ratio of oxygen that a tissue extracts from the blood to maintain morphological and functional integrity. Here, we present evidence from existing studies that …
Synergy Between Stenotrophomonas Maltophilia And Pseudomonas Aeruginosa During Polymicrobial Airway Infections, Melissa Skye Mcdaniel
Synergy Between Stenotrophomonas Maltophilia And Pseudomonas Aeruginosa During Polymicrobial Airway Infections, Melissa Skye Mcdaniel
All ETDs from UAB
Stenotrophomonas maltophilia is a Gram-negative bacillus that can act as an opportunistic pathogen in patients with respiratory diseases, including cystic fibrosis (CF) and ventilator-associated pneumonia. Infection with S. maltophilia is associated with worse lung function, but it remains unclear if this organism contributes directly to lung function decline. Lung infections are often polymicrobial, and S. maltophilia can be isolated from the lung with the key pulmonary pathogen Pseudomonas aeruginosa. In the first half of this work, we investigated the pathogenicity of S. maltophilia alone and during polymicrobial infection with P. aeruginosa. We used respiratory infections in mice to assess persistence …
Impact Of Nontypeable Haemophilus Influenzae And Pseudo Aeruginosa Polymicrobial Infections On The Cystic Fibrosis Lung, Natalie R. Lindgren
Impact Of Nontypeable Haemophilus Influenzae And Pseudo Aeruginosa Polymicrobial Infections On The Cystic Fibrosis Lung, Natalie R. Lindgren
All ETDs from UAB
Nontypeable Haemophilus influenzae (NTHi) is a Gram-negative commensal of the healthy nasopharynx; however, this organism can function as an opportunistic pathogen as a result of disruptions to the microbiome, as is the case in cystic fibrosis (CF) disease. People with CF experience changes in microbial residents of the respiratory tract over the course of their lifespan, seen in shifts from early-life pathogens, such as NTHi, to late-stage pathogens, such as Pseudomonas aeruginosa, that accompany a decrease in organismal diversity of the microbiome. In this work, we characterized the pathogenicity of NTHi alone and in polymicrobial respiratory infections. Using CF specific …
Study Of The Effects Of Contusion Spinal Cord Injury And Optogenetic Stimulation On Lower Urinary Tract Function, Salvador A. Lopez
Study Of The Effects Of Contusion Spinal Cord Injury And Optogenetic Stimulation On Lower Urinary Tract Function, Salvador A. Lopez
All ETDs from UAB
Lower urinary tract (LUT) dysfunction is a detrimental ailment that negatively affects a person’s independence, health, and overall quality of life. More specifically, LUT dysfunction as a result of spinal cord injury (SCI) is seen in more than 17,000 cases per year and of those cases, <20% are discharged from care with normal micturition1. Initially, after SCI, there is an acute period of spinal shock when the urinary bladder is flaccid and underactive, while the external urethral sphincter (EUS) that constricts the bladder outlet quickly becomes tonically active. In days to weeks after injury, spinallymediated, reflex bladder contractions re-emerge2-4. Numerous studies have examined aspects of LUT function using various models of SCI, primarily utilizing complete transection injuries. This set of studies first examined the effect of moderate to severe midthoracic contusion SCI on LUT function by examining cystometrogram (CMG) and EUS recordings, bladder/spinal cord morphology, sensory innervation of bladder tissue, and spinal neuronal activation in female mice. This model of SCI produced significant changes in normal bladder function as well as altered bladder morphology, including a robust loss of bladder afferent nerve fibers necessary for micturition. Inhibition of histone deacetylase 6 (HDAC6) has been shown to prevent the loss of sensory nerve fibers in mouse hind paw tissue5, thus HDAC6 inhibition was examined as a possible strategy to prevent the observed loss of sensory nerve fibers in bladder tissue post-SCI. iv Mice were treated using intraperitoneal injections of inhibiting compounds ACY-1083 (10 mg/kg) or Tubacin (5 mg/kg). Treatment resulted in significant improvements in CMG measures and sensory innervation of the bladder wall. Finally, optogenetic stimulation was examined using an adenoassociated virus containing cre-recombinase for cre-dependent expression of channelrhodopsin (ChR2) in both spinal intact and SCI mice. The ability to spare afferent axons in bladder tissue post-SCI through HDAC6 inhibition allowed ChR2 expression in sensory nerve fibers. Direct photostimulation of the bladder using various parameters of duration (1, 2, 5, 10 sec continuous stimulation) and power (0.1mW/mm2, 0.95mW/mm2, 6.50mW/mm2) resulted in the ability to control bladder contractions in both spinal intact (SI) and SCI animals, allowing for on-demand voiding post-injury.