ZHX2 in Podocyte Disease

 描述(申请人提供)：原发肾小球疾病，如局灶性和节段性肾小球硬化(FSGS)和微小病变病(MCD)是肾脏疾病人群中发病率的主要原因。FSGS患者通常进展到终末期肾功能衰竭。PI实验室的长期目标是开发新的基于机制的治疗剂，以减少由于肾小球疾病而导致的慢性肾脏疾病的进展。减少慢性肾脏疾病的进展到终末期肾脏疾病将在美国和世界范围内产生重大的积极的社会和财政影响。近八年前，PI的实验室首次公布了一个相对较新的转录因子家族--锌指和同源框(ZHX)蛋白在足细胞中的表达。在对所有三个家庭成员进行了十年的勤奋工作后，Pi和合作研究员对这个家庭的第二个成员ZHX2在肾小球疾病的背景下进行了几个有趣的观察。ZHX2似乎与足细胞细胞膜上的至少两种蛋白质相互作用。氨基肽酶A(APA)存在于足细胞的整个表面，而EPhin B1存在于裂隙隔膜中。本课题组的研究表明，ZHX2-APA关系可能是MCD发病的上游途径的基础，而ZHX2-EPhin B1的相互作用可能会非常显著地影响FSGS的发展。在具体目标1中，该团队将结合突变小鼠和人类疾病动物模型，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。在特定的目标2中，我们将测试ZHX2-ephin B1相互作用如何参与FSGS的发展。将使用几种突变的小鼠和动物模型。我们还将测试这种蛋白质相互作用是否可以与FSGS患者足细胞中表达的其他具有基因突变的蛋白质联系起来。在具体目标3中，将使用一种新的足细胞低水平ZHX2过表达的大鼠模型，为未来利用足细胞ZHX2表达增加来治疗人类肾小球疾病的治疗干预建立原理证据。

 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.