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

• 批准号: 9535605
• 负责人: EDWARD M MARCOTTE
• 金额: $ 6.18万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 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/9535605
• 关键词: Alleles; Apical; Biochemical; Biological; Biological Assay; Biological Process; Biology; Carrier Proteins; Cell physiology; Cells; Cellular Structures; Cellular biology; Chemicals; Cilia; Clinical; Co-Immunoprecipitations; Collaborations; Complement; Complex; Computer Simulation; 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; Hereditary Disease; Homology Modeling; Human; Image; Individual; Infant Mortality; Joubert syndrome; Kidney; Lead; Lesion; Limb structure; Maps; Mass Spectrum Analysis; Mediating; Medical Genetics; Microtubules; Modeling; Molecular; Multiprotein Complexes; Mus; Mutagenesis; Mutate; Mutation; Neuraxis; Oral; Organ; Organelles; Pattern; Phenotype; Play; Polydactyly; Positioning Attribute; Process; Protein Dynamics; Proteins; Proteomics; Recombinants; Recruitment Activity; Resolution; Role; Skeleton; Structural Models; Structure; Surface; Syndrome; System; Systems Biology; Testing; Time; Tubular formation; Work; Xenopus; base; brain tract; cell behavior; ciliopathy; cilium biogenesis; digital; experimental analysis; experimental study; fluid flow; human disease; imaging study; in vivo; in vivo imaging; insight; intercellular communication; kinetosome; network models; novel; planar cell polarity; protein complex; protein protein interaction; protein transport; reproductive tract; rib bone structure; success; tandem mass spectrometry

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.

摘要 纤毛是一种重要的细胞器，其功能包括从细胞间信号传递到体内平衡的产生。 管状器官中的液体流动。因此，一系列人类先天性疾病被描述为 “纤毛病”，因为它们共有纤毛结构或功能缺陷的病因学。尽管在这方面发挥了明显的作用， 中枢神经系统、四肢、中轴骨骼、肾脏、气道、大脑和生殖系统的破坏 道，我们的理解的机制，支配纤毛发生和纤毛介导的发育 图案仍然不完整。我们在这里建议研究一种新的多蛋白复合物的作用， 控制三个关键机制：基体对接，鞭毛内运输（IFT）招聘，和平面 电池极性（PCP）。我们将结合蛋白质组学、体内细胞生物学、小鼠遗传学和 人类疾病建模通过关注在发育和疾病中具有重要性的蛋白质， 但其作用机制尚不清楚，本文提出的实验将提供重要的新的 我们理解纤毛介导的发育模式的广度和深度，基体对接， 纤毛生物学中的新细胞生物学过程。反过来，这些发现应该提供更深入的了解， 先天性疾病，包括相对轻微的口-面-指综合征和完全致命的 短肋多指畸形。