ZHX2 in Podocyte Disease

ZHX2 在足细胞疾病中的作用

基本信息

批准号：
10001064
负责人：
Sumant Singh Chugh
金额：
$ 54.34万
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/10001064
关键词：
ANGPTL4 gene Albuminuria 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 Injections 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 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 Structure Surface Testing Therapeutic Therapeutic Agents Therapeutic Intervention Transcriptional Regulation Transgenic Organisms United States Up-Regulation Zinc Fingers base dimer glutamyl aminopeptidase human disease human model improved in vivo mRNA Expression migration mutant mouse model nephrotoxicity novel overexpression podocyte promoter protein expression public health relevance slit diaphragm social transcription factor

ANGPTL4 gene Albuminuria 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 Injections 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 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 Structure Surface Testing Therapeutic Therapeutic Agents Therapeutic Intervention Transcriptional Regulation Transgenic Organisms United States Up-Regulation Zinc Fingers base dimer glutamyl aminopeptidase human disease human model improved in vivo mRNA Expression migration mutant mouse model nephrotoxicity novel overexpression podocyte promoter protein expression public health relevance slit diaphragm social transcription factor

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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.

描述（由适用提供）：原发性肾小球疾病，如局灶性和节段性肾小球硬化（FSG）和最小变化疾病（MCD）是肾脏疾病人群发病率的主要原因。 FSGS患者通常会发展为终止肾脏衰竭。 PI实验室的长期目标是开发基于新机制的治疗剂，这些治疗剂将减少由于肾小球疾病而导致的慢性肾脏疾病的进展。减少慢性肾脏疾病到末期肾脏疾病的进展将在美国和全球范围内产生重大积极的社会和财务影响。 PI的实验室首先在大约八年前在足细胞中发表了相对新的转录因素，锌指和同源蛋白（ZHX）蛋白的表达。在勤奋地在所有三个家庭成员上工作了十年之后，PI和共同研究者在肾小球疾病的背景下对该家族的第二个成员ZHX2做出了一些有趣的观察。看来ZHX2与足细胞膜上至少两个蛋白质相互作用。蛋白酶A（APA）存在于整个足细胞表面上，而Ephrin B1存在于缝隙膜片中。我们小组进行的研究表明，ZHX2-APA关系可能构成MCD发病机理上游途径的基础，而Zhx2-磷蛋白B1相互作用可能会极大地影响FSG的发展。在特定目标1中，该团队将使用突变小鼠和人类疾病的动物模型的组合研究ZHX2-APA相互作用在MCD相关分子变化的发病机理中的重要性。在特定目标2中，我们将测试ZHX2-磷蛋白B1相互作用如何参与FSG的发展。将使用几种突变小鼠和动物模型。我们还将测试这种蛋白质相互作用是否可以与在FSGS患者中具有基因突变的足细胞中表达的其他蛋白质相关。在特定的目标3中，低水平ZHX2过表达的新大鼠模型将用于为未来的治疗干预措施建立原理证明，该干预措施利用增加的Podocyte ZHX2表达来治疗人肾小球疾病。