Discovery and characterization of novel ciliopathy protein complexes

摘要 纤毛疾病是一组衰弱的发育障碍(如Joubert综合征、Meckel综合征、 Bardet-Biedl综合征、口面部指征综合征、多囊肾病)，这些疾病没有治疗方法，而且有限 但是昂贵的治疗。纤毛疾病致多系统疾病诊断和治疗复杂 病理和临床表现有很大差异可能导致神经管缺陷， 口腔裂伤，肥胖，多囊肾，视网膜变性，在某些情况下，婴儿死亡。全 纤毛疾病是由纤毛功能障碍引起的，纤毛是一种基于微管的细胞器，对细胞间的信号传递至关重要， 但目前对导致适当纤毛的潜在分子网络的了解有限。 功能。最近，大规模的蛋白质组学技术已经发展到现在可以查询 细胞的分子网络，并鉴定许多新的蛋白质复合体。这份提案描述了一项研究 程序将1)使用蛋白质组技术构建纤毛复合体图谱，2)功能特征 新发现的纤毛复合体和3)确定由于已知的纤毛疾病导致的复合体组装的中断 突变。拟议研究的其他产品将包括一份蛋白质组数据概要 纤毛细胞，发现蛋白质复合体的统计分析工具，功能表征 关键的纤毛突起和对纤毛疾病潜在分子网络的更完整的理解 疾病状态。这项工作旨在为纤毛生物学提供一个重要的视角，以便更好地 了解纤毛疾病的复杂病因和分子病因，并可能开辟新的治疗方法 林荫道。

Abstract Ciliopathies are a collection of debilitating developmental disorders (e.g. Joubert syndrome, Meckel syndrome, Bardet-Biedl syndrome, orofaciodigital syndrome, polycystic kidney disease) which have no cures and limited but expensive treatments. Diagnosis and treatment is complicated due to ciliopathies causing multisystem pathologies and having large variance in their clinical presentations potentially resulting in neural tube defects, orofacial clefting, obesity, polycystic kidneys, retinal degeneration and in some cases, infant death. All ciliopathies are caused by dysfunctional cilia, the microtubule based organelle critical for cell-to-cell signaling, but currently there is limited understanding of the underlying molecular network responsible for proper cilia function. Recently, large-scale proteomic techniques have advanced where it is now possible to query the cell's molecular network and identify many new protein complexes. This proposal describes a research program that will 1) construct a ciliary complex map using proteomic techniques, 2) functionally characterize newly discovered ciliary complexes and 3) identify disruptions in complex assembly due to known ciliopathy mutations. Additional products of the proposed research will include a compendium of proteomic data on ciliated cells, statistical analysis tools for the discovery of protein complexes, functional characterization of critical ciliary processes and a more complete understanding of the underlying molecular network of ciliopathy disease states. This work aims to provide an important perspective of cilia biology in order to better understand the complex etiology and molecular causes of ciliopathies and potentially open new therapeutic avenues.