A SAM domain network in Polycystic Kidney Disease

多囊肾病中的 SAM 域网络

• 批准号: 8613279
• 负责人: JAMES U BOWIE
• 金额: $ 29.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8613279
• 关键词: Address; Affect; Animal Model; Architecture; Binding; Biochemical; Biological; Biological Process; Cell Polarity; Cell physiology; Cellular Assay; Complex; Cyst; Development; Diabetes Mellitus; Digestive System Disorders; Disease; Etiology; Funding Opportunities; Hematological Disease; Hereditary Disease; Human; Institutes; Interdisciplinary Study; Investigation; Investigator-Initiated Research; Kidney; Kidney Diseases; Kidney Failure; Lead; Liquid substance; Mediating; MicroRNAs; Mus; Mutation; NIH Program Announcements; Pathogenesis; Pathway interactions; Phenotype; Play; Polycystic Kidney Diseases; Proteins; Rat Strains; Rattus; Repression; Research Personnel; Research Project Grants; Resolution; Role; SAM Domain; Signal Transduction; Testing; Time; Transgenic Animals; Transgenic Organisms; Urologic Diseases; Work; base; biophysical properties; design; disease-causing mutation; experience; genetic regulatory protein; insight; mutant; new therapeutic target; novel therapeutic intervention; programs; protein complex; protein expression; protein function; protein protein interaction; public health relevance; research study; response; structural biology

PROJECT SUMMARY Polycystic kidney disease (PKD) is one of the most common lethal genetic diseases. Mutations in the Sterile Alpha Motif (SAM) domains of Bicaudal-C (Bicc1) and Samcystin/Anks6 are known to cause cystic disease in humans, rats or mice by unknown mechanisms. Prior work, and our own preliminary results, have established an interaction network between the SAM domains of Bicc1, Anks6 and a new protein we have identified called Anks3. Bicc1 regulates cell polarity and the expression of several proteins known to contribute to PKD. The fact that both Anks3 and Anks6 bind to the key regulatory protein Bicc1, suggests that they may be important for Bicc1 function. We propose to test two primary hypotheses: (1) That Anks6 and Anks3 can modulate the functions of Bicc1 either separately or together via there SAM domain interactions. (2) That the newly identified Anks3 protein can modulate the development of PKD. Aim 1. We will physically and structurally characterize the SAM mediated interactions of Bicc1, Ank3 and Anks6. An understanding of the architecture of the complexes will be important for understanding the biological consequences of SAM domain mutations. Aim 2. Test the hypothesis that Anks3 and Anks6 modulate known Bicc1 functions in cellular assays. We will examine the effects of Anks3 an Anks6 on cellular localization of Bicc1, protein expression and Wnt signaling. Aim 3. Test the hypothesis that Anks3 mutations can generate PKD in transgenic rats. Transgenic rat strains will be created where Anks3 is over-expressed or deleted and examined for the development of cystic disease. We will also study how these alterations affect the development of PKD in Anks6 mutant rats. The project has the potential to explain the mechanism of several disease-causing mutations, identify functions of proteins involved in PKD, and identify a new player in the complex pathway to PKD.

项目摘要 多囊性肾脏疾病（PKD）是最常见的致命遗传疾病之一。无菌突变 已知Bicauaudal-C（BICC1）和Samcystin/Anks6的α基序（SAM）结构域已知会引起囊性疾病 人类，大鼠或小鼠通过未知机制。先前的工作以及我们自己的初步结果已经建立 BICC1，ANKS6和我们已经确定的新蛋白质的SAM域之间的相互作用网络 anks3。 BICC1调节细胞极性和几种已知有助于PKD的蛋白质的表达。这 ANKS3和ANKS6都与关键调节蛋白BICC1结合的事实表明它们可能很重要 用于BICC1功能。我们建议测试两个主要假设：（1）ANKS6和ANKS3可以调节 BICC1的函数分别或通过那里的SAM域相互作用在一起。 （2）新确定的 ANKS3蛋白可以调节PKD的发展。 AIM 1。我们将在身体和结构上表征BICC1的SAM介导的相互作用ANK3 和Anks6。对综合体的建筑的理解对于理解 SAM结构域突变的生物后果。 AIM 2。检验ANKS3和ANKS6在细胞测定中调节已知BICC1功能的假设。 我们将研究ANKS3 A ANKS6对BICC1，蛋白表达和Wnt的细胞定位的影响 信号。 AIM 3。检验ANKS3突变可以在转基因大鼠中产生PKD的假设。转基因大鼠 将在ANKS3过度表达或删除并检查囊性开发的情况下创建菌株 疾病。我们还将研究这些改变如何影响ANKS6突变大鼠中PKD的发展。 该项目有可能解释几种引起疾病突变的机制，识别功能 涉及PKD的蛋白质，并在通往PKD的复杂途径中识别一个新玩家。