A SAM domain network in Polycystic Kidney Disease

多囊肾病中的 SAM 域网络

• 批准号: 9205230
• 负责人: JAMES U BOWIE
• 金额: $ 28.14万
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205230
• 关键词: ANK3 gene; Address; Affect; Animal Model; Applications Grants; Architecture; Binding; Biochemical; Biological; Biological Process; Cell Polarity; Cell physiology; Cellular Assay; Complex; Cyst; Development; Disease; Etiology; Funding Opportunities; Hematological Disease; Hereditary Disease; Human; Interdisciplinary Study; Investigation; Investigator-Initiated Research; Kidney; Kidney Diseases; Kidney Failure; Lead; Liquid substance; Mediating; MicroRNAs; Mus; Mutation; NIH Program Announcements; National Institute of Diabetes and Digestive and Kidney Diseases; Pathogenesis; Pathway interactions; Phenotype; Play; Polycystic Kidney Diseases; Proteins; Rat Strains; Rattus; Repression; Research Personnel; Research Project Grants; Resolution; Role; SAM Domain; Testing; Time; Transgenic Animals; Transgenic Organisms; Urologic Diseases; WNT Signaling Pathway; Work; biophysical properties; design; disease-causing mutation; experience; genetic regulatory protein; insight; mutant; new therapeutic target; novel therapeutic intervention; overexpression; programs; protein complex; protein expression; protein function; protein protein interaction; public health relevance; research study; response; structural biology

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：多囊肾病（PKD）是最常见的致命遗传病之一。 Bicaudal-C (Bicc1) 和 Samcystin/Anks6 的不育 Alpha 基序 (SAM) 结构域中的突变已知会通过未知机制在人类、大鼠或小鼠中引起囊性疾病。之前的工作以及我们自己的初步结果已经在 Bicc1、Anks6 的 SAM 结构域和我们确定的称为 Anks3 的新蛋白质之间建立了相互作用网络。 Bicc1 调节细胞极性和几种已知与 PKD 相关的蛋白质的表达。 Anks3 和 Anks6 均与关键调节蛋白 Bicc1 结合，这一事实表明它们可能对 Bicc1 功能很重要。我们建议测试两个主要假设：（1）Anks6 和 Anks3 可以通过 SAM 域相互作用单独或一起调节 Bicc1 的功能。 (2)新发现的Anks3蛋白可以调节PKD的发展。目标 1. 我们将从物理和结构上表征 Bicc1、Ank3 和 Anks6 的 SAM 介导的相互作用。了解复合物的结构对于理解 SAM 结构域突变的生物学后果非常重要。目标 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 和 Anks6 对 Bicc1 细胞定位、蛋白质表达和 Wnt 信号传导的影响。目标 3. 检验 Anks3 突变可在转基因大鼠中产生 PKD 的假设。将创建 Anks3 过度表达或缺失的转基因大鼠品系，并检查囊性疾病的发展情况。我们还将研究这些改变如何影响 Anks6 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，确定参与 PKD 的蛋白质的功能，并确定 PKD 复杂途径中的新参与者。

项目成果

ANKS3 Co-Localises with ANKS6 in Mouse Renal Cilia and Is Associated with Vasopressin Signaling and Apoptosis In Vivo in Mice.

• DOI: 10.1371/journal.pone.0136781
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Delestré L;Bakey Z;Prado C;Hoffmann S;Bihoreau MT;Lelongt B;Gauguier D
• 通讯作者: Gauguier D

CTGF Is Expressed During Cystic Remodeling in the PKD/Mhm (cy/+) Rat Model for Autosomal-Dominant Polycystic Kidney Disease (ADPKD).

CTGF 在常染色体显性多囊肾病 (ADPKD) PKD/Mhm (cy/ ) 大鼠模型的囊性重塑过程中表达。

• DOI: 10.1369/0022155417735513
• 发表时间: 2017
• 期刊: The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
• 作者: Gauer,Stefan;Holzmann,Yvonne;Kränzlin,Bettina;Hoffmann,SigridC;Gretz,Norbert;Hauser,IngeborgA;Goppelt-Struebe,Margarete;Geiger,Helmut;Obermüller,Nicholas
• 通讯作者: Obermüller,Nicholas

Exome sequencing and CRISPR/Cas genome editing identify mutations of ZAK as a cause of limb defects in humans and mice.

• DOI: 10.1101/gr.199430.115
• 发表时间: 2016-02
• 期刊: Genome research
• 影响因子: 7
• 作者: Spielmann M;Kakar N;Tayebi N;Leettola C;Nürnberg G;Sowada N;Lupiáñez DG;Harabula I;Flöttmann R;Horn D;Chan WL;Wittler L;Yilmaz R;Altmüller J;Thiele H;van Bokhoven H;Schwartz CE;Nürnberg P;Bowie JU;Ahmad J;Kubisch C;Mundlos S;Borck G
• 通讯作者: Borck G