Characterization of Par3(B) function in glomerular podocytes

肾脏过滤器疾病是终末期肾衰竭的主要原因，其社会经济负担不断上升。大多数已知的疾病起源于或影响足细胞，即形成肾脏滤过屏障外层的终末分化和高度极化的肾小球上皮细胞。足细胞形成的唯一的细胞间接触是相邻细胞之间的狭缝隔膜，它位于足细胞的基部。足细胞损伤的形态学特征是消失，足细胞结构简化，以肌动蛋白为基础的细胞骨架改变，细胞极性紊乱。我们和其他人已经证明aPKC/Par3/Par6极性信号复合体是连接细胞识别和极性信号通路的狭缝隔膜的一部分。在哺乳动物中，有两种Par3蛋白，Par3A和Par3B，它们起源于非常不同的基因表达。本研究小组未发表的数据显示，与大多数其他肾和非肾细胞相比，足细胞中的Par3B是主要的Par3蛋白。虽然我们对par3复合物的了解大多来自于对Par3A的研究，但对Par3B及其具体功能的了解却很少。在目前的提案中，我们利用小鼠和苍蝇模型生物的实验能力来(i)描述Par3B在肾小球滤过屏障的发育和维持中的功能，（ii）表征Par3B相互作用组和相关信号通路。然后，我们建议研究（iii）不同的Par3A和Par3B亚型及其在黑腹果蝇肾细胞中的生理相关性。我们相信，该研究项目极有可能对足细胞极性信号的调控产生新的见解，并具有治疗肾小球疾病的新治疗策略的潜力。

Diseases of the kidney filter are a leading cause of end stage renal failure with a consecutive rising socio-economic burden. Most known disorders originate from or affect the podocytes, terminally differentiated and highly polarized glomerular epithelial cells that form the outer layer of the kidney filtration barrier. The only cell-cell contact formed by podocytes is the slit diaphragm in between neighboring cells, which is localized at the basal part of the podocyte. The morphological feature of podocyte damage is effacement, the simplification of podocyte architecture with an altered actin based cytoskeleton and disturbed cellular polarity. We and others have shown that the aPKC/Par3/Par6 polarity-signaling complex is part of the slit diaphragm linking cell recognition and polarity signaling pathways. In mammals, there are two Par3 proteins, Par3A and Par3B, which originate from the expression of very different genes. Unpublished data from our group revealed that in contrast to most other renal and non-renal cells Par3B is the predominant Par3 protein in podocytes. While most of our understanding of the Par complex derives from work on Par3A very little is known about Par3B and its specific function. In the current proposal we take advantage of the experimental power of mouse and fly model organisms to (i) delineate the function of Par3B in development and maintenance of the glomerular filtration barrier and (ii) characterize the Par3B interactome and associated signaling pathways. We then propose to examine (iii) the different Par3A and Par3B isoforms and their physiological relevance in nephrocytes from Drosophila melanogaster. We believe, the proposed research project has a high likelihood to yield novel insights into the regulation of polarity signaling in podocytes and bears the potential for novel therapeutic strategies to treat glomerular disease.