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 多囊肾病是最常见的致死性遗传病之一。不育中的突变 已知Bicc 1和Samcystin/Anks 6的α基序（SAM）结构域在哺乳动物中引起囊性疾病。 人类、大鼠或小鼠通过未知的机制。先前的工作，以及我们自己的初步结果，已经建立了 Bicc 1、Anks 6的SAM结构域与我们发现的一种新蛋白质之间的相互作用网络， Anks 3. Bicc 1调节细胞极性和已知有助于PKD的几种蛋白质的表达。的 Anks 3和Anks 6都与关键调节蛋白Bicc 1结合，这一事实表明它们可能很重要 Bicc 1功能我们提出了两个主要假设：（1）Anks 6和Anks 3可以调节 Bicc 1的功能可以单独或通过SAM结构域相互作用一起发挥。(2)新发现的 Anks 3蛋白可调节PKD的发生发展。 目标1.我们将在物理和结构上表征SAM介导的Bicc 1、Ank 3 Anks6了解建筑群的结构对于理解 SAM结构域突变的生物学后果。 目标2.检验Anks 3和Anks 6在细胞测定中调节已知Bicc 1功能的假设。 我们将研究Anks 3和Anks 6对Bicc 1的细胞定位、蛋白表达和Wnt的影响。 发信号。 目标3.测试Anks 3突变可以在转基因大鼠中产生PKD的假设。转基因大鼠 将产生其中Anks 3过表达或缺失的菌株，并检查囊性癌的发展。 疾病我们还将研究这些改变如何影响Anks 6突变大鼠PKD的发展。 该项目有可能解释几种致病突变的机制， 蛋白质参与PKD，并确定一个新的球员在复杂的途径PKD。