Mapping the CPLANE interactome, an extensive protein interaction network underlying human ciliopathies

绘制 CPLANE 相互作用组图，这是人类纤毛病背后的广泛蛋白质相互作用网络

基本信息

批准号：
9179245
负责人：
EDWARD M MARCOTTE
金额：
$ 53.6万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-05 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9179245
关键词：
Alleles Apical Biochemical Biological Biological Assay Biological Process Biology Brain Carrier Proteins Cell physiology Cells Cellular Structures Cellular biology Cilia Clinical Co-Immunoprecipitations Collaborations Complement Complex Congenital Abnormality Data Defect Development Disease Disease model Docking Electron Microscopy Embryo Embryonic Development Etiology Europe Face Failure Foundations Fractionation Future Gap Junctions Generations Genes Genetic Genetic study Genotype Grant Homology Modeling Human Image Individual Infant Mortality Joubert syndrome Kidney Lead Lesion Life Limb structure Maps Mass Spectrum Analysis Mediating Medical Genetics Microtubules Modeling Molecular Mus Mutagenesis Mutate Mutation Neuraxis Oral Organ Organelles Pattern Phenotype Play Polydactyly Positioning Attribute Process Protein Dynamics Proteins Proteomics Recombinants Resolution Role Skeleton Structural Models Structure Surface Syndrome System Systems Biology Testing Time Tubular formation Work Xenopus base cell behavior ciliopathy cilium biogenesis digital experimental analysis fluid flow human disease in vivo in vivo imaging insight intercellular communication kinetosome network models novel planar cell polarity protein complex protein protein interaction reproductive tract research study rib bone structure success tandem mass spectrometry

项目摘要

ABSTRACT Cilia are essential organelles, with functions ranging from cell-cell signaling to the generation of homeostatic fluid flow in tubular organs. Consequently, an array of human congenital diseases has been characterized as “ciliopathies,” because they share an etiology of defective cilia structure or function. Despite manifest roles in the disruption of the central nervous system, limbs, axial skeleton, kidneys, airway, brain, and reproductive tracts, our understanding of the mechanisms that govern ciliogenesis and cilia-mediated developmental patterning remain incomplete. We propose here to study the roles of a novel multi-protein complex that controls three crucial mechanisms: basal body docking, IntraFlagellar Transport (IFT) recruitment, and Planar Cell Polarity (PCP). We will do so using a combination of proteomics, in vivo cell biology, mouse genetics and human disease modeling. By focusing on proteins with demonstrated importance in development and disease, but for which no mechanism of action is yet known, experiments proposed here will provide important new breadth and depth to our understanding cilia-mediated developmental patterning, basal body docking, and novel cell biological processes in ciliary biology. In turn, these findings should provide greater insight to a range of congenital diseases including both the relatively mild Oral-Facial-Digital syndrome and the wholly lethal Short Rib Polydactyly.

抽象的纤毛是必不可少的细胞器，功能范围从细胞细胞信号到体内平衡的产生管状器官中的流体流动。因此，一系列人类先天性疾病已被描述为 “纤毛病”，因为它们具有有缺陷的纤毛结构或功能的病因。尽管在明显的角色中中枢神经系统，四肢，轴向骨骼，肾脏，气道，大脑和生殖的破坏区域，我们对控制纤毛发生和纤毛介导的发育机制的理解图案仍然不完整。我们在这里建议研究一种新型多蛋白质复合物的作用控制三种至关重要的机制：基本身体对接，flagellar运输（IFT）招募和平面细胞极性（PCP）。我们将使用蛋白质组学，体内细胞生物学，小鼠遗传学和人类疾病建模。通过专注于在发育和疾病中表现出重要性的蛋白质，但是，对于尚未知道的动作机制，这里提出的实验将提供重要的新广度和深度，我们理解了Cilia介导的发展模式，基本身体对接和睫状生物学的新细胞生物学过程。反过来，这些发现应该为范围提供更大的见解先天性疾病，包括相对轻度口腔含量数字综合征和全致命的疾病短肋骨多结。