The Role of p120 Catenin in Metanephric Kidney Development

描述(由申请人提供)： 作为一名肾病学领域的内科科学家，我对肾脏的发育和疾病有着浓厚的兴趣。我的长期职业目标是了解肾脏发育中的细胞和分子事件，并将其转化为治疗急性肾损伤的临床相关疗法。我职业生涯的第二个目标是帮助阐明遗传性肾脏疾病的发病机制，如多囊肾病。为了实现这些目标，我提出了一个项目，重点是利用多囊疾病的小鼠模型来了解发育中的肾脏中细胞-细胞黏附和器官形态发生的动态。我的研究计划题为“p120连环蛋白在后肾发育中的作用”，旨在为实现我的目标提供一个框架。我的初步数据显示，新生的小鼠在肾脏中缺乏p120ctn，会出现肾囊肿和肾发育不良。我提出了三个具体目标来研究相关的细胞和分子机制。首先，我将检验一种假设，即由于细胞增殖、凋亡或细胞极性的改变，p120连环蛋白的丢失会导致多囊肾。这将通过生化和组织学方法在缺乏来自肾单位前体的p120连环素的小鼠中实现。使用类似的方法，我还将检验假设，即p120连接素的缺失导致肾发育不全，这是由于发育过程中间充质向上皮转化的缺陷导致肾单位形成减少所致。其次，我假设p120连环蛋白调节钙粘素水平和其他已知的细胞内信号通路，如Rho家族GTP酶和NF(B)信号。我将使用小鼠遗传学、免疫组织化学、生物化学和定量聚合酶链式反应来测试这一点。第三，我假设p120连环蛋白可能调节肾脏中尚未阐明的新的信号通路。我建议使用微阵列进行比较基因表达谱分析，以阐明新的信号通路。总而言之，这项建议旨在补充我以前的实验室经验，并为我提供成为一名独立调查人员的技术和智力工具。 公共卫生相关性：确定p120ctn在肾脏发育中的作用机制非常重要，这不仅是因为它将有助于阐明细胞黏附和上皮小管形成的正常机制，还因为它可能有助于揭示囊性疾病的发病机制。此外，识别后肾发育的分子和途径可能会增加对肾脏再生和修复的了解，并可能导致改进促进恢复的策略。

DESCRIPTION (provided by applicant): As a physician-scientist in the field of nephrology, I have a strong interest in development and disease in the kidney. My long-term career goals are to understand cellular and molecular events in kidney development and translate this into clinically relevant therapeutics for acute kidney injury. A second goal for my career is to help elucidate the pathogenesis of heritable kidney diseases, such as polycystic diseases. Toward these goals, I have proposed a project that focuses on understanding the dynamics of cell-cell adhesion and organ morphogenesis in the developing kidney using a mouse model of polycystic disease. My research proposal, entitled "The role of p120 catenin in metanephric kidney development", is constructed to provide a framework to achieve my goals. My preliminary data shows that newborn mice lacking p120ctn in nephrons develop kidney cysts and renal hypoplasia. I have proposed three specific aims to investigate the cellular and molecular mechanisms involved. First, I will test the hypothesis that loss of p120 catenin results in polycystic kidneys due to an alteration of cellular proliferation, apoptosis or cell polarity. This will be accomplished by biochemical and histological methods in mice lacking p120 catenin from nephron precursors. Employing similar methods, I also will test the hypothesis that loss of p120 catenin results in renal hypoplasia due to reduced nephron formation resulting from a defect in mesenchymal-to-epithelial transition during development. Second, I hypothesize that p120 catenin regulates cadherin levels and additional known intracellular signaling pathways, such as Rho family GTPases and NF(B signaling. I will test this using mouse genetics, immunohistochemistry, biochemistry and quantitative PCR. Third, I hypothesize that p120 catenin may regulate novel signaling pathways in the kidney that have not yet been elucidated. I propose to perform comparative gene expression profiling using microarrays to elucidate novel signaling pathways. Together this proposal is designed to complement my prior laboratory experiences and provide me with the technical and intellectual tools to become an independent investigator. PUBLIC HEALTH RELEVANCE: Defining the mechanisms of p120ctn's role in kidney development is important, not only because it will help elucidate the normal mechanisms of cell adhesion and epithelial tubulogenesis, but also because it may shed light on cystic disease pathogenesis. Furthermore, identification of the molecules and pathways that underlie metanephric development may increase understanding of renal regeneration and repair and may lead to improved strategies for enhanced recovery.