Diseases Commons^™

Exploring Drivers Of Sex-Based Disparities In Relapsing Multiple Sclerosis, Stephanie K. Buxhoeveden

Theses and Dissertations

Females are three times more susceptible to relapsing multiple sclerosis (MS) and males typically have more severe disease, but the molecular underpinnings of these sex-based disease disparities are unknown and represent a critical knowledge gap.Subject Population: Blood samples from a demographically homogenous group of treatment naïve males and females with relapsing-MS and healthy controls. Research Design: Cross-sectional combinatorial omics pilot study. Instruments: Whole transcriptomic analysis with messenger RNA (mRNA) expression profiling using next generation sequencing (RNA-seq) and micro-RNA (miRNA) expression using NanoString technology. Aim 1) Identify and compare the actively expressed mRNAs in the transcriptome of males and …

Infiltrating Cd8+ T Cells Exacerbate Alzheimer’S Disease Pathology In A 3d Human Neuroimmune Axis Model, Jefin Jose, Devam Purohit

VCU's Medical Journal Club: The Work of Future Health Professionals

In this study, Jorfi et al. employed a neuroimmune axis model containing neurons, astrocytes, and microglia to examine the role of immune cells in Alzheimer's disease. Jorfi et al. found that T cells selectively infiltrated the BRAIN compartment of the neuroimmune axis model as compared to B cells and monocytes. Jorfi et al. further found that CD8+ T cells demonstrated heightened cytotoxicity in the Alzheimer's disease brain, illuminating the role of immune cells in neurodegeneration. Upon further examination, the CXCR3-CXCL10 signaling pathway was found to have an important role in inflammation.

A Genome-Wide In Vivo Crispr Screen Identifies Essential Regulators Of T Cell Migration To The Cns In A Multiple Sclerosis Model, Jefin Jose

VCU's Medical Journal Club: The Work of Future Health Professionals

Kendirli et al. (2023) used a CRISPR screen to determine the proteins involved in T cell migration into the CNS in multiple sclerosis. Overall, eighteen facilitators and five brakes to T cell infiltration into the CNS were identified. Kendirli et al. specifically identified ITGA4, FERMT3, and HSP90B1 to make up the adhesion module, CXCR3, GNAI2, and TBX21 to make up the chemotaxis module, and GRK2 and S1PR2 to make up the egress module. This study demonstrated the ability of a CRISPR screen to identify elements in a disease process and thus identify targets for future multiple sclerosis therapies.

Structural Changes In Neurons In Multiple Sclerosis, Saad Bhatti

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

No abstract provided.

Investigating Cannabinoid Type-1 Receptor (Cb1r) Positive Allosteric Modulators (Pams) In Mouse Models Of Overt Cannabimimetic Activity, Subjective Drug Effects, And Neuropathic Pain, Jayden Elmer

Theses and Dissertations

Chronic pain affects between 20 and 30 percent of the adult population in western countries and represents a wide array of specific etiologies (Berge, 2011). Neuropathic pain secondary to traumatic nerve injury, chemotherapeutic toxicity, or diseases (e.g., diabetes mellitus) is often refractory to conventional analgesics, with patients receiving less than 50% pain relief compared to placebo (Finnerup et al. 2010). The endocannabinoid system has shown potential as a therapeutic target for neuropathic pain wherein CB1 agonism via administration of exogenous agonists or pharmacological blockade of endocannabinoid catabolic enzymes exhibits efficacy in reversing allodynia in the chronic constriction injury (CCI) model …

Ectopic Pregnancy In A Woman With T9 Ais A Paraplegia Secondary To High-Grade Spinal Cord Pilocytic Astrocytoma, Elisabeth K. Acker

Graduate Medical Education (GME) Resident and Fellow Research Day Posters

Ectopic pregnancy in a woman with T9 AIS A (motor complete, sensory complete) paraplegia secondary to a high-grade spinal cord pilocytic astrocytoma

Background

In the United States, 20,000 women of childbearing age have a spinal cord injury (SCI). While SCI induces transient amenorrhea immediately after injury, women generally have normal reproductive function after SCI, and their fertility is unimpaired. Medications that commonly manage complications of SCI should be avoided or discontinued during pregnancy. Complications inherent to SCI, including urologic issues, are often exacerbated during pregnancy.

Methods

This is a case report on a female Veteran who initially presented to the …

Recovery From Visual Dysfunction Following Mild Traumatic Brain Injury Is Associated With Adaptive Reorganization Of Retinal Inputs To Lateral Geniculate Nucleus In The Mouse Model Utilizing Central Fluid Percussion Injury., Vishal C. Patel

Theses and Dissertations

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality nationwide. Prevalence of mild TBI (mTBI) vastly outnumbers more severe forms however the associated morbidity has only recently gained public attention. Visual dysfunction is a significant component of mTBI associated morbidity with recovery of function linked with improvement in global outcomes. Examination of sensory and motor pathways in other brain injury paradigms support that recovery is largely dependent on adaptive plasticity of remaining connections. Current examinations of visual function recovery following mTBI is limited to identifying evidence for recovery and objective evidence for adaptive plasticity is limited. Therefore, …

Ndrg1 And Myelin-Related Disease: Alcoholism And Chemotherapy-Induced Neuropathy, Guy Harris

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Our laboratory has implicated N-myc down-regulated gene 1 (Ndrg1) as a potential candidate gene that modulates ethanol-induced changes in myelin-related gene expression and acute sensitivity to ethanol. Analysis of …

Exploring The Heteromeric Interface Of The 5-Ht2a-Mglu2 Receptor Complex, Mohamed Aarif Abdul Kareem

Theses and Dissertations

Schizophrenia is a serious mental disorder characteristic of several neurotransmitters including dopamine, serotonin, and glutamate being in imbalance. Early therapies focused solely on dopamine antagonism and second-generation antipsychotics focused on the dopamine and serotonin systems and their respective G protein coupled receptor (GPCR) proteins. Although debate for dimerization of certain classes of GPCR exist, the establishment of an mGlu2-5-HT_2A heterocomplex, which is implicated in schizophrenia is of interest. Previous studies have used a mutation-based approach to identify transmembrane domain 4 (TM4) as the domain responsible in mGlu2 for mediating heteromerization before narrowing down the individual amino acids responsible for …

Role Of Sarm1 In Chronic Immune-Mediated Central Nervous System Inflammation, Kenneth E. Viar Ii

Theses and Dissertations

SARM1 is an injury-induced nicotinamide adenine dinucleotide nucleosidase (NADase) that was previously shown to promote axonal degeneration in response to traumatic, toxic, and excitotoxic stressors. This raises the question of whether a SARM1-dependent program of axonal degeneration is central to a common pathway contributing to disease burden in neurological disorders. The degree to and mechanism by which SARM1 inactivation decreases the pathophysiology of such disorders is of interest to establish the rationale to pursue SARM1 as a therapeutic target. In this study, we compare the course and pathology of experimental autoimmune encephalomyelitis (EAE) in Sarm1-knockout (KO) mice and wild-type …

The Role Of Syndecan-1 And Extracellular Vesicles In Breast Cancer Brain Metastasis, Megan R. Sayyad

Theses and Dissertations

Breast cancer metastasizes to the brain in 15-30% of all breast cancer cases, and metastasis is the predominant cause of breast cancer-related deaths. Patients with HER2-enriched and triple-negative breast cancers (TNBCs) are more likely to develop brain metastases. While targeted therapies exist for HER2-enriched breast cancers, there are no effective treatments for TNBCs. Thus, a greater understanding of how these cancers spread to the brain is critical. In order to spread to the brain, disseminated breast cancer cells must overcome 2 major steps—crossing the blood-brain barrier (BBB) and survival and successful colonization of the distinctive and mostly cellular brain environment. …

Long-Term Effects Of Notch1 Signaling On Neural Stem Cells Following Traumatic Brain Injury, Cruz Sevilla Jr

Theses and Dissertations

Traumatic brain injury (TBI) is a devastating problem which stands as a leading cause of death and disability. The elderly is significantly affected by TBI, typically as the result of falls, and recovery is especially limited. This, in part, is associated with decreased tissue-specific stem cell regeneration and replacement of damaged cells in the aged brain. The diminished ability of the aged brain to recover is especially devastating after TBI, likely leading to permanent loss of sensory, motor, and cognitive functions. Studies have shown that the mature mammalian brain contains Neural Stem Cells (NSCs), found in specific regions of the …

Altered Axon Initial Segment Structure And Function In Inflammatory Disease, Kareem C. Clark

Theses and Dissertations

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal insults remain unclear. While most axonal pathologies characterized in MS are a direct consequence of myelin loss, we propose that axonal pathologies also occur independent of demyelination. In support of this idea, we recently reported that mice that develop experimental autoimmune encephalomyelitis (EAE), a model commonly used to mimic the pathogenesis of MS, exhibit a structural and functional disruption of the axon initial segment (AIS), a subdomain of the axon that …

Design, Synthesis, And Biological Screening Of Selective Mu Opioid Receptor Ligands As Potential Treatments For Opioid Addiction, Samuel Obeng

Theses and Dissertations

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling …

Reverse Engineering A Kinetic Model Of A Dopaminergic Neuron To Apoptosis, Johnathan Morris

Biology and Medicine Through Mathematics Conference

No abstract provided.

Post-Tbi Hippocampal Neurogenesis In Different Tbi Models, Kaushal S. Patel

Theses and Dissertations

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years …

A Mechanistic Study Of An Ipsc Model For Leigh’S Disease Caused By Mtdna Mutataion (8993 T>G), John P. Galdun

Theses and Dissertations

Mitochondrial diseases encompass a broad range of devastating disorders that typically affect tissues with high-energy requirements. These disorders have been difficult to diagnose and research because of the complexity of mitochondrial genetics, and the large variability seen among patient populations. We have devised and carried out a mechanistic study to generate a cell based model for Leigh’s disease caused by mitochondrial DNA mutation 8993 T>G. Leigh’s disease is a multi-organ system disorder that depends heavily on the mutation burden seen within various tissues. Using new reprogramming and sequencing technologies, we were able to show that Leigh’s disease patient fibroblasts …

The Effect Of Optogenetic Manipulation Of Ss Interneurons Within Malformed, Epileptogenic Cortex, Nicole Ekanem

Theses and Dissertations

A large percentage of individuals with intractable epilepsies have an accompanying cortical malformation, the underlying cellular mechanisms of which are poorly understood. It is known however that in an animal model for one such malformation, polymicrogyria, epileptogenesis occurs most easily from an adjacent area termed the paramicrogyral region (PMR). Previous studies implicate SS interneurons as a potential contributor to this pathology, which lead to our hypothesis: in PMR, SS interneurons exert a higher modulatory influence on excitatory pyramidal cells, as compared to the same by SS interneurons within homologous control cortex.

Using a freeze-lesion model for polymicrogyria in transgenic mice …

Axon Initial Segment Stability In Multiple Sclerosis, Suneel K. Thummala

Theses and Dissertations

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS …