Discovery and characterization of novel ciliopathy protein complexes

新型纤毛病蛋白复合物的发现和表征

基本信息

批准号：
10438895
负责人：
Kevin Drew
金额：
$ 24.44万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438895
关键词：
Affect Alleles Animal Model Bardet-Biedl Syndrome Biochemical Biological Biological Models Biology Cells Cilia Cilium Microtubule Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collection Complement Complex Computational Biology Congenital Abnormality Data Data Analyses Data Set Development Developmental Cell Biology Diagnosis Disease Embryo Etiology Exhibits Fractionation Future Gene Transfer Techniques Human Ion Exchange Joubert syndrome Link Machine Learning Maintenance Maps Mass Spectrum Analysis Meckel-Gruber syndrome Mentors Molecular Molecular Sieve Chromatography Mus Mutation Neural Tube Defects Obesity Organelles Orofaciodigital Syndromes Pathology Patients Polycystic Kidney Diseases Property Proteins Proteomics Rana Recording of previous events Regulation Research Retinal Degeneration Role Sea Anemones Sea Urchins Severity of illness Signal Transduction Statistical Data Interpretation Structural Models Structure of ciliary processes Syndrome Systems Biology Techniques Testing Therapeutic Tissue Microarray Tissues Training Work Xenopus laevis base cell type ciliopathy clinically relevant developmental disease educational atmosphere fly human disease in vivo in vivo imaging infant death insight large scale data loss of function machine learning pipeline novel novel therapeutics orofacial cleft particle programs protein complex protein function skills success tool

项目摘要

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.

抽象的纤毛病是一系列使人衰弱的发育障碍（例如朱伯特综合征、梅克尔综合征、 Bardet-Biedl 综合征、口面指综合征、多囊肾病）无法治愈且效果有限但治疗费用昂贵。纤毛病引起多系统疾病，诊断和治疗复杂病理学和临床表现有很大差异，可能导致神经管缺陷，口面部裂、肥胖、多囊肾、视网膜变性，在某些情况下还导致婴儿死亡。全部纤毛病是由纤毛功能失调引起的，纤毛是一种基于微管的细胞器，对细胞间信号传导至关重要，但目前对负责适当纤毛的底层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步，现在可以查询细胞的分子网络并识别许多新的蛋白质复合物。该提案描述了一项研究程序将 1) 使用蛋白质组学技术构建睫状复合体图谱，2) 功能表征新发现的纤毛复合体，3) 识别已知纤毛病导致的复合体组装中断突变。拟议研究的其他产品将包括蛋白质组数据纲要纤毛细胞，用于发现蛋白质复合物的统计分析工具，功能表征关键的纤毛过程以及对纤毛病的潜在分子网络的更全面的了解疾病状态。这项工作旨在提供纤毛生物学的重要视角，以便更好地研究了解纤毛病的复杂病因和分子原因，并可能开辟新的治疗方法途径。