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

绘制纤毛相互作用组图谱，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：
10649416
负责人：
EDWARD M MARCOTTE
金额：
$ 57.88万
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 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649416
关键词：
Alleles Apical Biochemical Biogenesis Biological Assay Biological Models Biology Carrier Proteins Cell physiology Cells Cellular Structures Cellular biology Central Nervous System Chlamydomonas Cilia Classification Clinical Collaborations Complement Complex Computer Models Congenital Abnormality Data Data Set Defect Development Disease Docking Electron Microscopy Embryonic Development Etiology Europe Face Family suidae Future Generations Genes Genetic Goals Grant Human Human Genetics Image In Vitro Infant Mortality Joubert syndrome Kidney Knowledge Lead Limb structure Link Maps Mass Spectrum Analysis Measures Meckel-Gruber syndrome Mediating Medical Genetics Microtubules Modeling Mutation Oral Organ Organelles Organism Pattern Polydactyly Process Proteins Proteome Proteomics Role Sampling Skeleton Structural Models Structure Surface Syndrome Testing Tetrahymena Tissues Trachea Tubular formation Variant Work Xenopus base brain tract ciliopathy cilium biogenesis comparative crosslink digital experimental study fluid flow human disease in vivo innovation insight intercellular communication kinetosome model organism mouse genetics novel protein complex protein structure recruit reproductive tract rib bone structure success superresolution microscopy three-dimensional modeling

项目摘要

SUMMARY 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 clear roles in the development 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, not least because hundreds of different proteins are required for proper cilia biogenesis and function, acting via an extensive interaction network containing diverse proteins of unknown function. We propose here to study several large multi-protein assemblies that are essential for proper cilia formation in order to determine the roles of these complexes in key steps in ciliogenesis, including recruitment of proteins to the basal body, intraflagellar transport and recruitment of specific intraflagellar cargoes. This grant combines directed mechanistic experiments, proteomics, 3D modeling, in vivo cell biology, and testing of human disease alleles in model organisms to understand mechanisms by which key ciliary proteins and their interaction partners effect proper cilia formation, and how specific mutations in these genes lead to birth defects. 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 and novel cell processes in ciliary biology. In turn, these findings should provide greater insight to a range of congenital diseases ranging from the relatively mild Oral-Facial-Digital syndrome to the wholly lethal Short Rib Polydactyly.

概括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。尽管在开发中枢神经系统，四肢，轴向骨骼，肾脏，气道，大脑和生殖区域，我们对控制纤毛发生和纤毛介导的发育机制的理解构图仍然不完整，尤其是因为适当的纤毛需要数百种不同的蛋白质生物发生和功能，通过包含未知的潜水蛋白的广泛相互作用网络作用功能。我们在这里建议研究几个对于适当纤毛必不可少的大型多蛋白组件为了确定这些复合物在纤毛发生中的关键步骤中的作用，包括募集蛋白质到基本体内的蛋白质，氟法内的运输和特定的flaglagllar货物的募集。这格兰特结合了定向的机械实验，蛋白质组学，3D建模，体内细胞生物学和测试模型生物中的人类疾病等位基因，以了解关键睫状蛋白及其关键睫状蛋白的机制相互作用伴侣影响适当的纤毛形成，以及这些基因中的特定突变如何导致出生缺陷。通过专注于在发育和疾病中表现出重要性的蛋白质，但没有行动机理尚不知道，此处提出的实验将为重要的新广度和深度提供我们理解纤毛介导的发育模式和睫状生物学的新细胞过程。反过来，这些发现应该为一系列相对较中的先天性疾病提供更大的见解对完全致命的短肋骨多结的口服数字综合征。

项目成果

期刊论文数量（43）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Photoredox-Catalyzed Decarboxylative C-Terminal Differentiation for Bulk- and Single-Molecule Proteomics.

DOI：
10.1021/acschembio.1c00631
发表时间：
2021-11-19
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Zhang, Le;Floyd, Brendan M.;Chilamari, Maheshwerreddy;Mapes, James;Swaminathan, Jagannath;Bloom, Steven;Marcotte, Edward M.;Anslyn, Eric, V
通讯作者：
Anslyn, Eric, V

Integration of over 9,000 mass spectrometry experiments builds a global map of human protein complexes.

DOI：
10.15252/msb.20167490
发表时间：
2017-06-08
期刊：
Molecular systems biology
影响因子：
9.9
作者：
Drew K;Lee C;Huizar RL;Tu F;Borgeson B;McWhite CD;Ma Y;Wallingford JB;Marcotte EM
通讯作者：
Marcotte EM

Protein Sequencing, One Molecule at a Time.