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

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（由申请人提供）：原发性肾小球疾病，如局灶性和节段性肾小球硬化症（FSGS）和微小病变病（MCD）是肾病患者发病的主要原因，从长远来看，这些疾病通常会进展为终末期肾衰竭。 PI 实验室的目标是开发基于新机制的治疗药物，以减少因肾小球疾病导致的慢性肾病的进展。终末期肾病将对美国和全世界产生重大的积极社会和经济影响 PI 实验室首次发表了近 8 个足细胞中相对较新的转录因子家族的表达，即锌指和同源盒 (ZHX) 蛋白。几年前，在对所有三个家族成员进行了十年的辛勤研究后，PI 和合作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。 ZHX2 与足细胞细胞膜上的至少两种蛋白质相互作用，氨肽酶 A (APA) 存在于整个足细胞表面，而 Ephrin B1 则存在于狭缝隔膜中。我们小组进行的研究表明 ZHX2-APA 关系。可能构成 MCD 发病机制上游途径的基础，而 ZHX2-Ephrin B1 相互作用可能会极大地影响 FSGS 的发展。在具体目标 1 中，研究小组将结合突变小鼠和人类疾病动物模型来研究 ZHX2-APA 相互作用在 MCD 相关分子变化发病机制中的重要性。在具体目标 2 中，我们将测试以了解其如何发挥作用。 ZHX2-ephrin B1 相互作用参与 FSGS 的发展，我们还将使用几种突变小鼠和动物模型来测试这种蛋白质相互作用是否可以与患有基因突变的患者的足细胞中表达的其他蛋白质联系起来。 FSGS。在具体目标 3 中，足细胞低水平 ZHX2 过表达的新大鼠模型将用于为未来利用增加足细胞 ZHX2 表达治疗人类肾小球疾病的治疗干预措施建立原理证明。