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RESCUE OF ALPORT SYNDROME OTOPATHOLOGY

阿尔波特综合征的拯救耳病理学

基本信息

批准号：
9214327
负责人：
Dominic E. Cosgrove
金额：
$ 47.44万
依托单位：
FATHER FLANAGAN'S BOYS' HOME
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-03 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9214327
关键词：
Address Age Animals Basement membrane Binding Bioenergetics Biomechanics Blood capillaries CDC42 gene Cell Line Cells Cochlea Cochlear duct Collagen Computer software Deposition Disease Disease Progression Drops Drug Targeting Dysmorphology Ear Endothelial Cells Endothelin A Receptor Endothelin-1 Environment Event Extracellular Matrix Filopodia Focal Adhesion Kinase 1 Frequencies Functional disorder Gelatinase A Gene Expression Genes Glomerular Capillary Glomerular Mesangial Cell Hereditary nephritis Hypoxia Immunofluorescence Immunologic In Vitro Inflammatory Invaded Kidney Diseases Kidney Failure Kidney Glomerulus Labyrinth Laminin Lateral Life Longevity MAPK8 gene Matrix Metalloproteinases Measures Mediating Metabolic Metabolic stress Metabolism Metalloproteases Mitochondria Molecular Mus Na(+)-K(+)-Exchanging ATPase Nature Noise Noise-Induced Hearing Loss Oxides PTK2 gene Paper Pathogenesis Pathologic Pathology Pathway interactions Permeability Phenotype Physiological Predisposition Proteins Proteinuria RNA Receptor Signaling Reduced Glutathione Renal glomerular disease Reverse Transcriptase Polymerase Chain Reaction SLC2A1 gene Sensorineural Hearing Loss Series Signal Pathway Signal Transduction Stress Stretching Stria Vascularis Symptoms Testing Thick Time Transcript United States National Institutes of Health Vascular Endothelial Growth Factors Vascular Permeabilities Wild Type Mouse Work capillary cytokine gene induction glomerular basement membrane hearing impairment in vivo interstitial laminin alpha 2 laminin alpha1 laminin alpha5 mouse model podocyte prevent public health relevance rho GTP-Binding Proteins small molecule inhibitor

项目摘要

DESCRIPTION (provided by applicant): Alport syndrome is characterized by renal disease associated with sensorineural hearing loss. While much is known about the molecular nature of Alport glomerular and interstitial kidney disease, the mechanisms underlying the hearing loss phenotype remain relatively underexplored. In a series of recent papers and some unpublished results, we have revealed a mechanism for glomerular disease initiation involving activation of endothelin-1 that activates the formation of mesangial filopodia through the endothelin A receptor (ETAR). The filopodia invade the capillaries progressively leaving punctate deposits of mesangial matrix proteins, including laminin 211, in the glomerular basement membrane (GBM). The laminin 211 activates focal adhesion kinase on podocytes, leading to maladaptive gene expression that drives glomerular pathogenesis. Inhibiting this pathway by blocking ETAR has a profound effect on glomerular disease progression in the mouse model. As in the GBM, the strial capillary basement membranes (SCBMs) gradually thicken in Alport mice. These events result in a hypoxic environment in the scala media and a sensitivity to noise-induced hearing loss with a significant drop in the endocochlear potential (EP), proving that in the mouse, hearing loss is due to strial dysfunction. We show preliminary evidence that endothelin-1, laminin 211, collagen α1(IV), and laminin α5 are up-regulated in the stria vascularis of Alport mice relative to wild type mice, and are associated with FAK activation. Endothelin A receptors (ETARs) are present on strial marginal cells, and ETAR blockade prevents SCBM thickening and accumulation of matrix in the SCBM. Our central hypothesis is: Treatment of Alport mice with the ETAR antagonist Sitaxentan will prevent SCBM thickening and normalize strial function, preventing hearing loss and protecting animals from the inner ear metabolic stresses and pathology normally associated with Alport syndrome in the mouse model. We will address this in four specific aims: In the first we will determine whether ETAR blockade in the mouse model normalizes expression of ECM proteins and MMPs, SCBM thickness and permeability. In the second aim we will utilize a strial marginal cell line to probe the mechanism of ET-1 induction and ETAR signaling as it relates to induction of genes encoding ECM and MMPs. In the third we will determine whether normalization of SCBM thickness via ETAR blockade results in normalization of endocochlear potentials (EPs) and protection from noise induced hearing loss. Lastly, we will determine whether we have achieved metabolic rescue and return of normoxia by measuring noise induced mitochondrial ROS, oxidized/reduced glutathione ratios, and ATP levels in the stria of Alport mice compared to Alport mice under ETAR blockade. The discovery of this pathway suggests that a single drug target, in this case small molecule inhibitors that block ETAR, may provide a means of ameliorating both the glomerular and inner ear pathologies associated with Alport syndrome.