Discovery and characterization of novel ciliopathy protein complexes

摘要 纤毛病是使人衰弱的发育障碍（例如Joubert综合征、Meckel综合征、 Bardet-Biedl综合征、口面指综合征、多囊肾病），这些疾病无法治愈， 但是昂贵的治疗。由于睫状体病引起多系统损害，诊断和治疗较为复杂 病理学并且在它们的临床表现中具有大的差异可能导致神经管缺陷， 口面裂、肥胖、多囊肾、视网膜退化，在某些情况下，婴儿死亡。所有 纤毛病是由纤毛功能障碍引起的，纤毛是基于微管的细胞器，对细胞间信号传导至关重要， 但目前对负责纤毛的潜在分子网络的了解有限， 功能最近，大规模蛋白质组学技术取得了进展，现在可以查询蛋白质组。 细胞的分子网络，并确定了许多新的蛋白质复合物。该提案描述了一项研究 该程序将1）使用蛋白质组学技术构建睫状体复合物图谱，2）功能表征 新发现的纤毛复合体和3）鉴定由于已知的纤毛病引起的复合体组装的破坏 突变。拟议研究的其他产品将包括蛋白质组学数据汇编， 纤毛细胞，发现蛋白质复合物的统计分析工具， 关键的纤毛过程和更完整的了解潜在的分子网络的纤毛病变 疾病状态。这项工作旨在提供纤毛生物学的重要视角，以便更好地 了解复杂的病因学和纤毛病变的分子原因，并可能开辟新的治疗方法， 大道。

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.