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ZHX2 in Podocyte Disease

ZHX2 在足细胞疾病中的作用

基本信息

批准号：
9353800
负责人：
Sumant Singh Chugh
金额：
$ 56.02万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
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：
2016-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353800
关键词：
ANGPTL4 gene Albuminuria Alpha Cell Animal Model Antibodies BALB/cJ Mouse Backcrossings Binding Biology Buffaloes Cell Nucleus Cell membrane Chronic Kidney Failure Co-Immunoprecipitations Cytoplasmic Tail Development Dimerization Disease Disease Pathway Dose End stage renal failure Endogenous Retroviruses Ephrin-B1 Family Family member Focal Segmental Glomerulosclerosis Foot Process Future Gatekeeping Gene Mutation Genes Genetic Transcription Goals Homo Human Inbred BALB C Mice Injection of therapeutic agent Integral Membrane Protein Introns Kidney Diseases Kidney Failure Knockout Mice Laboratories Link Mass Spectrum Analysis Mediating Mediator of activation protein Minor Modeling Molecular Morbidity - disease rate Mouse Strains Mus Nephrotoxic Nuclear Nuclear Localization Signal Pathogenesis Pathway interactions Patients Peripheral Phase Play Population Proteins Proteinuria Publishing Rattus Renal glomerular disease Research Personnel Role Serum Site-Directed Mutagenesis Surface Testing Therapeutic Therapeutic Agents Therapeutic Intervention Transcriptional Regulation Transgenic Organisms United States Up-Regulation Zinc Fingers base dimer glutamyl aminopeptidase human disease improved in vivo mRNA Expression migration mutant mouse model nephrotoxicity novel overexpression podocyte promoter protein expression public health relevance slit diaphragm social transcription factor

项目摘要

DESCRIPTION (provided by applicant): Primary glomerular diseases like focal and segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are a major cause of morbidity in the kidney disease population. FSGS patients often progresses to end stage kidney failure. The long term goal of the PI's lab is to develop novel mechanism - based therapeutic agents that will reduce the progression of chronic kidney disease due to glomerular disorders. Reducing the progression of chronic kidney disease to end stage kidney disease will have a major positive social and financial impact in the United States and worldwide. The PI's laboratory first published the expression of a relatively new family of transcriptional factors, th zinc Fingers and Homeoboxes (ZHX) proteins, in podocytes nearly eight years ago. After working diligently on all three family members for a decade, PI and co-investigator have made several interesting observations about the second member of this family, ZHX2, in the context of glomerular diseases. It appears that ZHX2 interacts with at least two proteins present on the podocyte cell membrane. Aminopeptidase A (APA) is present over the entire podocyte surface, whereas Ephrin B1 is present in the slit diaphragm. Studies conducted by our group suggest that the ZHX2-APA relationship may form a basis for upstream pathways in the pathogenesis of MCD, whereas the ZHX2-Ephrin B1 interaction could potentially very significantly influence the development of FSGS. In Specific Aim 1, the team will investigate the importance of the ZHX2-APA interaction in the pathogenesis of MCD related molecular changes using a combination of mutant mice and animal models of human disease. In Specific Aim 2, we will test to see how the ZHX2-ephrin B1 interaction participates in the development of FSGS. Several mutant mice and animal models will be used. We will also test if this protein interaction can be linked with other proteins expressed in podocytes that have gene mutations in patients with FSGS. In Specific Aim 3, a new rat model of low level ZHX2 overexpression in podocytes will be used to establish proof of principle for future therapeutic interventions that utilize increasing podocyte ZHX2 expression to treat human glomerular diseases.