ZHX2 in Podocyte Disease

 描述（由申请方提供）：原发性肾小球疾病，如局灶性节段性肾小球硬化（FSGS）和微小病变病（MCD）是肾脏疾病人群发病的主要原因。FSGS患者通常进展为终末期肾衰竭。PI实验室的长期目标是开发新的基于机制的治疗药物，以减少肾小球疾病引起的慢性肾脏疾病的进展。减少慢性肾脏疾病向终末期肾脏疾病的进展将在美国和世界范围内产生重大的积极社会和经济影响。PI的实验室首次发表了一个相对较新的转录因子家族的表达，锌指和同源异型盒（ZHX）蛋白，在足细胞近八年前。在对所有三个家族成员进行了十年的辛勤工作后，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ZHX 2进行了一些有趣的观察。似乎ZHX 2与足细胞膜上存在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，而肝配蛋白B1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发病机制中上游途径的基础，而ZHX2-Ephrin B1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，研究小组将使用突变小鼠和人类疾病动物模型的组合，研究ZHX 2-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ZHX2-ephrin B1相互作用如何参与FSGS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联。在具体目标3中，足细胞中低水平ZHX 2过表达的新大鼠模型将用于建立未来治疗干预的原理证明，这些干预利用增加足细胞ZHX 2表达来治疗人类肾小球疾病。

 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.