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The Role Of Biomaterial Substrate In Stem Cell Fate Determination, Zhenjie Liu

Wayne State University Dissertations

The physical cues, which included topography, stiffness, and mechanical forces, can influence the stem cell renewal, differentiation, and maturation in vivo and in vitro. The nano-topography of the ECM can stimulate the neural differentiation of the stem cells, while the micro-topography of the ECM can guide the neurite outgrowth. However, the role and functional size of the micro- and nano-topography in the stem cell fate determination is not clear yet. To study this aim, two biomaterial based aligned fiber platforms (ACMFP and ASMFP) were designed, fabrication and evaluated to cover the micro-, submicro-, and nano-fiber topography, which used to study …

Cardio-Renal Mechanisms Of Fructose-Induced Salt-Sensitive Hypertension, Peter Eric Levanovich

Wayne State University Dissertations

Dietary consumption of fructose facilitates increased intestinal fluid absorption and renal sodium reabsorption, thereby increasing fluid retention. The net result of this is a sustained increased in extracellular fluid volume that leads to states of hypervolemia and subsequent hypertension. Simultaneously, arterial pressure is being elevated by increased autonomic drive stemming from the sympathetic nervous system and various other endovascular proteins that induce vasoconstriction. Under these conditions, the addition of high dietary sodium promotes hypertension prior to the development of significant metabolic disturbances; the subtlety of which may go unnoticed by patients for prolonged periods. While much is understood regarding the …

Clinical Significance, Functional Role And Molecular Mechanism Of 2’-O-Methyltransferase Ftsj3 In Promoting Cancer Progression, Morenci Manning-Powell

Wayne State University Dissertations

2’-O-methylation (2’-O-Me), one of the most common modifications within RNA, has multiple roles in modulating RNA structure, stability, and interactions, as well as gene transcription and translation. We previously performed integrative genomic and transcriptomic analysis of 58 RNA methyltransferases, and identified FTSJ3 (FtsJ RNA 2ʹ-O-methyltransferase 3) as significantly amplified/overexpressed in breast cancer. Knockdown of FTSJ3 inhibits breast cancer cell growth in vitro. However, the clinical significance, functional role, and molecular mechanism of FTSJ3 in human cancer remains to be elucidated. In the present study, we first analyzed the differential mRNA and protein expression of FTSJ3 between tumor and normal tissues …

The Dynamics Of Life And Death: Mitochondrial Fragmentation, Mitophagy, And Swelling During Neuronal Ischemia/Reperfusion Injury, Anthony Roy Anzell

Wayne State University Dissertations

Ischemic brain injury caused by cardiac arrest or stroke continue to be leading caused of death and disability in the U.S. While restoration of blood flow is necessary to salvage ischemic tissue, reperfusion paradoxically exacerbates injury via the production of reactive oxygen species, which, damage mitochondria and induce cell death. Therefore, it is critical to have stringent quality control mechanisms to ensure a healthy mitochondrial network. Mitochondrial fragmentation has been well characterized in the progression of ischemia/reperfusion and its association with cell death. Conversely, the role of mitophagy has been controversial regarding whether upregulation of mitophagy serves as a restorative …

Causes And Potential Treatment For Altered Muscle Metaboreflex Control Of Ventricular Vascular Interactions In Heart Failure, Joseph Thomas Mannozzi

Wayne State University Dissertations

Muscle Metaboreflex Activation occurs as a result of metabolic accumulation within active skeletal muscle that stimulates type III and IV afferents. This reflex in healthy subjects causes increased ventricular contraction, tachycardia, enhanced central blood volume mobilization, and 2 mediated vasodilation as a means to increase mean arterial pressure and thereby improve perfusion pressure of active skeletal muscle. However, to date no study has evaluated the interaction between the observed changes in ventricular and vascular dynamics or how the reflex impacts contraction relaxation dynamics before and after induction of heart failure Furthermore, no study has evaluated the impact of chronic selective …

Testosterone And Interpersonal Attraction: A Placebo-Controlled Design, Stefan M. Goetz

Wayne State University Dissertations

Testosterone has long been implicated as a neuroendocrinological mechanism in the expression of reproductive strategies. Humans the world over form and maintain pair-bonds suggesting that pair-bonds may serve to enhance reproductive fitness. However, infidelity is a perennial threat to these bonds. The data in humans suggests that testosterone is associated with mate-seeking but may be detrimental to relationship maintenance. However, past work has relied on correlational studies and additional findings from nonhuman animal models suggest that acute changes rather than baseline concentrations in testosterone may in fact protect extant pair-bonds. The present research sought to test the causal role of …

Assessment Of Presumed Sterility Of The Human Placenta And Maternal Bladder, Ali Alhousseini

Wayne State University Dissertations

Introduction

Preterm birth is the number one cause of neonatal morbidity and mortality. A causal link has been established between infection and preterm birth. Urinary tract infection is the number one infection in pregnancy. Evaluating the existence of a placental and maternal bladder microbiome is a major scientific and clinical milestone in perinatal medicine.

Methodology and Results

Chapter 2: This is a prospective case control study. 69 placentas were collected in a sterile fashion from six groups of women without infection: Term cesarean not in labor (n=18), term cesarean in labor (n=9), term vaginal (n=21), preterm cesarean not in labor …

Stress-Dependent Regulation Of A Major Node Of The Insulin-Like Peptide Network That Modulates Survival, Rashmi Chandra

Wayne State University Dissertations

Chronic stress disrupts insulin signaling, predisposing human populations to diabetes, cardiovascular disease, Alzheimer’s Disease, and other metabolic and neurological disorders, including post-traumatic disorders (PTSD). Thus, efficient recovery from stress optimizes survival. However, stress recovery in humans is difficult to study, but is much easier to dissect in model organisms. The worm genetic model Caenorhabditis elegans can switch between stressed and non-stressed states, and this switch is largely regulated by insulin signaling. Previously, the Alcedo lab proposed that insulin-like peptides (ILPs), which exist as multiple members of a protein family in both C. elegans and humans, implements a combinatorial coding strategy …

Molecular Mechanisms In Cftr-F508del Degradation And The Functional Defect Of Cftr Absence In Rabbits, Carthic Rajagopalan

Wayne State University Dissertations

Cystic Fibrosis (CF) is the most common, lethal autosomal recessive disorder, and is caused by mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR), an anion channel that is found in most epithelial cells lining the airway and gut. The most common mutation of CFTR is deletion of phenylalanine at position 508 (CFTR-F508del), which produces a misfolded protein. Through the ubiquitin proteasome system (UPS), this misfolded protein is ubiquitinated and signaled for degradation via the cytosolic proteasome. Previous studies demonstrating experimental restoration of F508DEL-CFTR trafficking to the plasma membrane showed partial function of the chloride channel, raising therapeutic speculations. …

Molecular Machinery For The ‘Kiss And Run’ Mechanism Of Insulin Secretion, Akshata Ramesh Naik

Wayne State University Dissertations

The insulin secreting porosome is a supramolecular lipo-protein complex that

measures roughly 100 – 120 nm in diameter. Porosomes allow transient fusion of insulin

secretory granules to the cell plasma membrane and mediates partial release of secretory

contents. Post secretion, the secretory granule reseals and re-enters to the cell interior.

This is in contrast to the ‘total fusion’ phenomenon, where secretory vesicles completely

fuse at the cell plasma membrane and release all of the contents to the cell exterior. This

study involved a deeper understanding of the transient or ‘kiss-and-run’ mechanism of

cell secretion that involves the insulin secreting porosome …

The Balance Between Prostaglandin E2 Ep3 And Ep4 Receptors Determines Severity Of Cardiac Damage In Myocardial Infarction And An Angiotensin Ii-Induced Model Of Hypertension, Timothy Dean Bryson

Wayne State University Dissertations

According to the center for disease control about 610,000 people die every year in the United States from heart disease, of which, coronary heart disease is the most common form. One major risk factor for heart attack is hypertension, which affects nearly half of all Americans [472, 473]. PGE2 plays an important role in regulating cardiovascular function and mediating inflammation, both of which contribute to the development of hypertension and/or heart disease. Prostaglandin E2 can act as a vasodilator or vasoconstrictor depending on which of its receptor subtypes are activated.

In general, activation of the EP1 and EP3 receptors is …

Appropriate Preconditioning Of The Uterine Endoplasmic Reticulum Stress Response Inhibits Preterm Labor, Judith Ann Ingles

Wayne State University Dissertations

Introduction: In this study, we are testing the overarching hypothesis that preconditioning the myometrial UPR allows for the maintenance of non-apoptotic CASP3 activity and thus sustains uterine quiescence. We have previously demonstrated that the pregnant uterus facilitates uterine quiescence through UPR mediated activation of non-apoptotic CASP3, yet the mechanism in which CASP3 utilizes to avoid its apoptotic cell fate is unresolved. There is a growing body of evidence including our own that demonstrates remote and direct preconditioning with minor stresses propagates cytoprotective mechanisms that allow for the avoidance of apoptotic cell death upon exposure to a subsequent more damaging stress, …

Sensitivity Of Quagga Mussels (Dreissena Rostriformis Bugensis) To Cyanobacteria At Multiple Life History Stages, Anna Boegehold

Wayne State University Dissertations

Quagga mussels (Dreissena rostriformis bugensis) originate from brackish waters of the Ponto-Caspian area and are nuisance invasive species in North American and European freshwaters. Their invasion has caused major economic and ecological damages in the Laurentian Great Lakes. Through selective filter feeding, quagga mussels have promoted the growth of cyanobacteria. Harmful cyanobacteria blooms have the potential to produce toxins, which can be toxic to humans and wildlife. Although quagga mussels can increase the prevalence of cyanobacteria blooms, it is unknown how they are physiologically affected by cyanobacteria and understanding these dynamics can be useful in the management of this invasive …

The Role Of Alström Syndrome 1 (Alms1) In Hypertension, Salt Sensitivity And Metabolic Syndrome, Keyona Nicole King-Medina

Wayne State University Dissertations

In humans, inactivating mutations in the Alström syndrome 1 (ALMS1) gene cause obesity, insulin resistance and hypertension (metabolic syndrome). More so, SNPs in the ALMS1 gene have been associated with kidney disease and cardiovascular disease. The

mechanisms causing these alterations are unclear. We recently found that the ALMS1 is expressed in the kidney thick ascending limb (TAL) where it mediates endocytosis of the renal Na/K/2Cl cotransporter termed NKCC2. To study the role of ALMS1 in renal

physiology we generated ALMS1 knockout (KO) rats in a Dahl salt-sensitive genetic background via zinc-finger nuclease targeting. We previously found that the amount of …

Remote Preconditioning: Evaluating The Efficacy Of Cardioprotection In Type-2 Diabetes And Exploring The Mechanistic Role Of Exosomes, Joseph Michael Wider

Wayne State University Dissertations

Remote preconditioning is a promising and robust treatment for myocardial

ischemia/reperfusion injury that evokes cardioprotection through endogenous neural

and/or humoral signaling. A recent study has reported that protective signaling is

mediated by exosomes through the circulation; however this concept is supported by

limited and inconsistent evidence. Despite overwhelming success in preclinical studies,

the efficacy of remote preconditioning in human studies is inconclusive. Importantly, the

majority of remote preconditioning studies use healthy animal models despite growing

evidence that comorbidities, such as type-2 diabetes, may negatively influence

outcomes. Nonetheless, the efficacy of remote preconditioning in the setting of type-2

diabetes has not …

Circadian Modulation Of Breathing Stability And Respiratory Plasticity, Mohamad El Chami

Wayne State University Dissertations

Purpose: Our project was designed to determine the effect of time of day on multiple mechanisms influencing breathing stability and respiratory plasticity. We investigated if the number and duration of breathing events coupled to upper airway collapsibility, as well as the carbon dioxide reserve, chemoreflex sensitivity and arousal threshold during non-rapid eye movement (NREM) sleep were affected by the time of day. In addition, we examined if mild intermittent hypoxia (IH) initiates long-term facilitation of upper airway muscle activity leading to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events.

Methods: Male participants with obstructive …

Activity Dependent Changes In Functional And Morphological Characteristics Among Presympathetic Neurons Of The Rostral Ventrolateral Medulla, Daniel J. Huereca

Wayne State University Dissertations

A sedentary lifestyle is a major risk factor for the development of cardiovascular disease (CVD), the leading cause of death among Americans. Increasing evidence implicates increased sympathetic nerve activity (SNA) as the link between a sedentary lifestyle and CVD. The research presented in this dissertation examines the region of the brainstem known as the rostral ventrolateral medulla (RVLM) and how its regulation of SNA changes as a result of sedentary conditions. Our group has previously reported that sedentary conditions enhance splanchnic SNA in response to pharmacologically induced decreases in blood pressure or by direct activation of the RVLM via microinjection …

Role Of Alström Syndrome 1 (Alms1) In Nkcc2 Endocytosis, Thick Ascending Limb Function, Blood Pressure Regulation And Metabolic Function, Ankita Bachhawat Jaykumar

Wayne State University Dissertations

NaCl absorption by the Thick Ascending Limb (TAL) is mediated by the apical Na+/K+/2Cl- co-transporter, NKCC2. Increased NKCC2 activity and apical trafficking are associated to salt sensitive hypertension in rodents and humans. NKCC2 endocytosis is important for maintaining surface NKCC2 such that blocking NKCC2 endocytosis increased NKCC2 surface abundance and NKCC2-mediated NaCl reabsorption. Despite its importance, NKCC2 endocytosis has been poorly studied and a part of the reason may be attributed to the lack of availability of methods with good time resolution. Hence, we developed a method to image apical NKCC2 to monitor its endocytosis in real-time by Total Internal …

Human Kinome In Skeletal Muscle Insulin Resistance, Yue Qi

Wayne State University Dissertations

Protein kinases play fundamental roles in regulation of biological processes and functions, such as insulin signaling and glucose metabolism. Dysregulation of protein kinases may cause impaired cell signaling and human diseases, such as metabolic syndrome and type 2 diabetes (T2D). Skeletal muscle is the main site responsible for insulin-stimulated glucose disposal, and insulin resistance in skeletal muscle is one of the key features of the pathogenesis of T2D. Therefore, malfunction of protein kinases and their interaction proteins may contribute to the molecular mechanism of insulin resistance in human skeletal muscle. However, no large scale profiling study has been reported to …

Estimating The Variables Of The Nonlinear Dynamical Theory Of Acute Cell Injury, Fika Tri Anggraini

Wayne State University Dissertations

This Dissertation is the first to estimate the variables D and S of the nonlinear theory of acute cell injury in hippocampal regions CA1 and CA3 using a rat model of global brain ischemia and reperfusion (I/R). D was estimated by quantifying protein aggregates using ubiquitin Western blotting. S was estimated by quantifying changes in polysomal mRNAs as measured by microarray chips. D and S time courses were sampled at 0.5, 8, 16, 24, 48, and 72 hrs of reperfusion after 10 min brain ischemia. CA1 dies and CA3 survives. The theory predicts D will be larger in CA1 and …

The Role Of Pparγ In Placental Development And Disease, Leena Kadam

Wayne State University Dissertations

The placenta in mammals forms the maternal fetal interface serving as the source of nutrition for the fetus throughout gestation. It comprises of two major trophoblast lineages: (i) the decidua invading extra-villous trophoblast (EVT) and (ii) the placenta residing villous trophoblast (VT). The EVT’s invade the maternal endometrium to establish pregnancy and secure blood-flow to the implantation site. The VT villous trophoblast forms the main maternal-fetal exchange surface and ensures nutrient and gas exchange to facilitate growth throughout pregnancy. Additionally, both lineages are involved in immunological functions such as maintaining allogenic tolerance and regulation of immune cell activation at the …

The Digestive Composition And Physiology Of Water Mites, Adrian Amelio Vasquez

Wayne State University Dissertations

Water mites are a diverse group of arachnids that inhabit aquatic habitats and have been studied in the past for their biodiversity, unique lifecycle, bioindicator species use and for their impact as parasites on insects of human pathological significance such as the mosquito. Water mites are critical in their environment as possible apex predators however, their life cycle and morphological complexity has made taxonomy and description of water mites difficult. Although water mite species richness is estimated at over 6000 species described to date, descriptions of extant North American water mite species are estimated to be only 50% of the …

Calponin And Cytoskeleton Dynamics In Macrophage Functions And The Pathogenesis Of Atherosclerosis, Rong Liu

Wayne State University Dissertations

Arterial atherosclerosis is an inflammatory disease. Macrophages play a major role in the pathogenesis and progression of atherosclerotic lesions. Modulation of macrophage function is a therapeutic target for the treatment of atherosclerosis. Calponin is an actin-filament-associated regulatory protein that inhibits the activity of myosin-ATPase and dynamics of the actin cytoskeleton. Encoded by the Cnn2 gene, calponin isoform 2 is expressed at significant levels in macrophages. Deletion of calponin 2 increases macrophage migration and phagocytosis. In the present study, we investigated the effect of deletion of calponin 2 in macrophages on the pathogenesis and development of atherosclerosis. The results showed that …

Muscle Metaboreflex And Arterial Baroreflex: Action, Interaction And Altered Control In Heart Failure, Jasdeep Kaur

Wayne State University Dissertations

Stimulation of skeletal muscle afferents by metabolites that accumulate in the exercising muscle elicits a large pressor response, termed the muscle metaboreflex. Muscle metaboreflex activation during submaximal exercise induces large increases in arterial pressure, cardiac output, heart rate and ventricular contractility however, the vascular responses have varied in previous studies. We addressed three specific questions: 1) what are the mechanism(s) regulating the non-ischemic vasculature during muscle metaboreflex activation in normal subjects, 2) whether muscle metaboreflex activation vasoconstricts the ischemic active muscle from which this reflex originates and if this vasoconstriction is exaggerated in heart failure and 3) how do the …

An Analysis Of Plasticity In The Rat Respiratory System Following Cervical Spinal Cord Injury And The Application Of Nanotechnology To Induce Or Enhance Recovery Of Diaphragm Function, Janelle Lorien Walker

Wayne State University Dissertations

Second cervical segment spinal cord hemisection (C2Hx) results in ipsilateral hemidiaphragm paralysis. However, the intact latent crossed phrenic pathway can restore function spontaneously over time or immediately following drug administration.

WGA bound fluorochromes were administered to identify nuclei associated with diaphragm function in both the acute and chronic C2Hx models. WGA is unique in that it undergoes receptor mediated endocytosis and is transsynaptically transported across select physiologically active synapses. Comparison of labeling in the acutely injured to the chronically injured rat provided an anatomical map of spinal and supraspinal injury induced synaptic plasticity. The plasticity occurs over time in the …

The Role Of Oxidative Stress In The Establishment Of Resistance To Cisplatin In Epithelial Ovarian Cancer Cells, Jimmy Belotte

Wayne State University Dissertations

Epithelial ovarian cancer is the deadliest of all gynecologic cancers with an estimated 22,280 new cases and 14,240 deaths expected in 2016 in the US alone. This high mortality rate can be partially attributed to a lack of universal screening and the development of resistance to the recommended chemotherapeutics. Typically, the treatment of ovarian cancer requires both cytoreductive surgery (CRS) and platinum/taxane combination chemotherapy. Initially, 50–80% of patients with advanced disease will achieve complete clinical response. Unfortunately, most will relapse within 18 months with chemoresistant disease. Thus, understanding the mechanisms of platinum resistance is critical in order to improve the …

The Impact Of Myeloperoxidase And Its Related Oxidants On Metaphase Ii Mouse Oocyte Quality, Faten Nuri Shaeib

Wayne State University Dissertations

Inflammatory reactions mediated by oxidative stress (OS) have been implicated in the deterioration of oocyte quality, which may lead to subfertility. Oxidative stress generated from enhancement of activated macrophages secondary to an inflammatory response are the major source of reactive oxygen species (ROS) such as superoxide (O2•−), hydrogen peroxide (H2O2), hydroxyl radical (•OH), and hypochlorous acid (HOCl), as well as, the pro-inflammatory enzyme myeloperoxidase (MPO). Previously, it has been shown that these ROS have deleterious effect on oocytes; however the link between inflammation through macrophage activity and oocyte quality remains unclear. In this work, we investigated: 1) the mechanism through …

The Role Of Alarmins, Invariant Nkt Cells And Senescence In The Pathophysiology Of Sterile Intra-Amniotic Inflammation, Olesya Plazyo

Wayne State University Dissertations

Preterm birth is defined as the delivery of a live baby prior to the 37th week of gestation. It is the leading cause of neonatal mortality worldwide. Preterm neonates are at a higher risk for short- and long-term complications, and prematurity places significant burden on our society. Elucidation of the mechanisms that lead to spontaneous preterm labor will enable development of therapies to prevent this syndrome. We aimed to study pathological inflammation that is implicated in the pathophysiology of spontaneous preterm labor.

Pathological inflammation can be initiated by the activation of innate immunity either by microorganisms or alarmins, which are …

Role Of Secretory Granule Heterogeneity In Calcium-Triggered Exocytosis, Tejeshwar Rao

Wayne State University Dissertations

The sympathetic nervous system is activated by a variety of threats to organismal homeostasis. The adrenomedullary chromaffin cell is the core effector of sympathetic activity in the peripheral nervous system. By design, the chromaffin cell secretory response is mutable so that release can be rapidly tuned to drive context-dependent changes in physiological function. However, the mechanisms by which this tuning is achieved with such high temporal fidelity and context specificity remain unclear. This represents a major gap in our understanding of the sympatho-adrenal system since it is known to modify the function of nearly every organ system in the body. …

Unstable Ventilatory Control During Sleep After High Spinal Cord Injury: The Contribution Of Chemosensitivity And Hypoventilation, Amy Therese Bascom

Wayne State University Dissertations

ABSTRACT

UNSTABLE VENTILATORY CONTROL DURING SLEEP AFTER HIGH SPINAL CORD INJURY: THE CONTRIBUTION OF CHEMOSENSITIVITY AND HYPOVENTILATION

by

Amy T. Bascom

May 2015

Advisor: Dr. Harry G. Goshgarian

Major: Anatomy and Cell Biology

Degree: Doctor of Philosophy

A high prevalence of sleep-disordered breathing (SDB) after spinal cord injury (SCI) has been reported in the literature; however, the underlying mechanisms are not well understood. My studies had 2 aims: 1) to determine the effect of the withdrawal of the wakefulness drive to breathe on the degree of hypoventilation in SCI patients and able-bodied controls and 2) to determine the response of …