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Structural basis of BBSome-mediated ciliary exit

BBSome介导的纤毛退出的结构基础

基本信息

批准号：
10624912
负责人：
Maxence V Nachury
金额：
$ 70.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10624912
关键词：
Address Affect Bardet-Biedl Syndrome Binding Biochemical Biological Assay Blindness Cattle Cells Cilia Clathrin Adaptors Complex Computer software Cryoelectron Microscopy Data Defect Disease Erinaceidae Eukaryotic Cell Excision Functional disorder Future G-Protein-Coupled Receptors GTP Binding Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Hair Health Hereditary Disease Human Ice Image Knowledge Light Maps Mediating Membrane Membrane Proteins Modeling Molecular Molecular Conformation Movement Mutation Obesity Palliative Care Pathogenicity Pathway interactions Patients Peptides Photoreceptors Polydactyly Proteins Receptor Signaling Regulation Resolution Retina Retinal Degeneration Retinal Dystrophy SSTR3 gene Side Signal Pathway Signal Transduction Signaling Molecule Smell Perception Solid Structural Models Structure TFAP2A gene Testing Therapeutic Intervention Training Transcription Factor AP-1 Variant Vertebral column Vision Work ciliopathy conformer gene replacement therapy gene therapy insight kidney malformation morphogens novel therapeutic intervention particle pre-clinical preclinical trial protein complex recruit smoothened signaling pathway therapeutically effective trafficking

项目摘要

PROJECT SUMMARY Primary cilia organize signaling pathways such as vision, olfaction and Hedgehog signaling. Proper functioning of these pathways is critically dependent on the movements of molecules into, inside and out of cilia, yet our understanding of the basic mechanisms governing trafficking through cilia remains fragmentary. Past work from the lab identified and characterized the BBSome, a protein complex that ferries signaling receptors out of cilia and clears photoreceptor outer segments of unwanted proteins. The relevance of the BBSome to human health and disease is evidence by the fact that BBSome dysfunction causes Bardet-Biedl Syndrome (BBS), a hereditary disease characterized by obesity, retinal degeneration, polydactyly and kidney malformations. The major goal of this proposal is to determine the structure and function of the molecular cogs and levers within the BBSome that enable selective removal of proteins from cilia. The proposed studies will cast new light on ciliary trafficking and lay the basis of future therapeutic interventions.

项目概要初级纤毛组织信号传导途径，例如视觉、嗅觉和刺猬信号传导。正常运作这些途径的关键取决于分子进出纤毛的运动，然而我们的对通过纤毛进行贩运的基本机制的了解仍然不完整。过去的工作实验室鉴定并表征了 BBSome，这是一种蛋白质复合物，可将信号受体从纤毛并清除光感受器外段不需要的蛋白质。 BBSome 与人类的相关性 BBSome 功能障碍会导致 Bardet-Biedl 综合征 (BBS)，这是健康和疾病的证据。以肥胖、视网膜变性、多指畸形和肾脏畸形为特征的遗传性疾病。该提案的主要目标是确定分子齿轮和杠杆的结构和功能在 BBSome 内，能够选择性地去除纤毛中的蛋白质。拟议的研究将带来新的曙光纤毛贩运并为未来的治疗干预奠定基础。