The Role of p120 Catenin in Metanephric Kidney Development

p120 连环蛋白在后肾肾发育中的作用

基本信息

批准号：
8294847
负责人：
DENISE K MARCIANO
金额：
$ 14.85万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8294847
关键词：
Accounting Actins Acute Renal Failure with Renal Papillary Necrosis Adherens Junction Alleles Apoptosis Binding Biochemical Biochemistry Biological Cadherins Cell Adhesion Cell Polarity Cell Proliferation Cell surface Cell-Cell Adhesion Cells Cilia Complement Complex Cyst Cystic kidney Cytoskeleton Data Defect Development Disease Distal E-Cadherin Embryo Epithelial Event Extracellular Domain Failure Family Family member Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Health Human Immunohistochemistry Individual Investigation Kidney Kidney Diseases Knock-out Laboratories Lead Light Link Mediating Mesenchymal Mesenchyme Metanephric Diverticulum Methods Molecular Morphogenesis Mus Mutant Strains Mice Mutate Natural regeneration Nephrology Nephrons Newborn Infant Oligonucleotide Microarrays Organ Partner in relationship Pathogenesis Pathway interactions Penetrance Phenocopy Phenotype Physicians Play Polycystic Kidney Diseases Proteins Recovery Regulation Research Personnel Research Proposals Reverse Transcriptase Polymerase Chain Reaction Role Scientist Signal Pathway Signal Transduction Staging Surface Testing Therapeutic Tissues Transcriptional Regulation Transduction Gene Transgenic Mice Translating Western Blotting adhesion receptor career catenin p120ctn protein cell motility cell type clinically relevant comparative design epithelial to mesenchymal transition experience improved in vivo interest mouse model mutant nephrogenesis novel recombinase repaired rho tool tumor progression

项目摘要

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.

描述（由申请人提供）：作为肾脏学领域的医师科学家，我对肾脏的发育和疾病有浓厚的兴趣。我的长期职业目标是了解肾脏发育中的细胞和分子事件，并将其转化为急性肾脏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可遗传的肾脏疾病的发病机理，例如多囊疾病。朝向这些目标，我提出了一个项目，该项目专注于使用多囊病小鼠模型在发育中的肾脏中细胞细胞粘附和器官形态发生的动力学。我的研究建议题为“ p120 catenin在跨肾脏肾脏发展中的作用”，旨在提供一个实现我目标的框架。我的初步数据表明，肾单位缺乏P120CTN的新生小鼠会出现肾脏囊肿和肾功能低下。我提出了三个特定目的，以研究涉及的细胞和分子机制。首先，我将检验以下假设：由于细胞增殖，凋亡或细胞极性的改变，p120 catenin导致多囊肾脏导致多囊肾脏。这将通过缺乏肾单位前体中缺乏P120 catenin的小鼠的生化和组织学方法来实现。使用类似的方法，我还将检验以下假设：p120 catenin的丧失导致肾脏发育不全，这是由于发育过程中间充质到上皮过渡的缺陷导致的肾单位形成降低。 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建议使用微阵列进行比较基因表达分析，以阐明新的信号通路。公共卫生相关性：定义P120CTN在肾脏发育中的作用的机制很重要，这不仅是因为它有助于阐明细胞粘附和上皮管造成的正常机制，还可以阐明囊性疾病发病机理。此外，鉴定基于跨载体发展的分子和途径可能会增加对肾脏再生和修复的理解，并可能导致改进的策略以增强恢复。