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A SAM domain network in Polycystic Kidney Disease

多囊肾病中的 SAM 域网络

基本信息

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
项目类别：
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

项目摘要

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.

项目总结