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Identifying Signaling Mechanisms Controlling Flagellar Length in Chlamydomonas

识别衣藻中控制鞭毛长度的信号机制

基本信息

批准号：
8211405
负责人：
PRACHEE AVASTHI
金额：
$ 5.13万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8211405
关键词：
Affect Back Bardet-Biedl Syndrome Biological Assay Cell physiology Cells Chlamydomonas Chlamydomonas reinhardtii Cilia Cilium Microtubule Complex Cytoplasm Defect Disease Distal Environment Feedback Flagella Fluorescence Resonance Energy Transfer G-Protein-Coupled Receptors Genes Genetic Genetic Screening Genomics Green Algae Green Fluorescent Proteins Hydrocephalus Insertional Mutagenesis KRP protein Kinetics Length Light Lipase Liquid substance Maintenance Mammalian Cell Maps Methods Microtubules Mitogen-Activated Protein Kinases Modeling Molecular Motor Movement Nephronophthisis Organelles Organism Partner in relationship Pathologic Pathology Pathway interactions Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Play Polycystic Kidney Diseases Process Proteins Public Health RNA Interference Recycling Regulation Retinal Degeneration Role Sensory Signal Transduction Signaling Molecule Signaling Protein Source Structure Surface Swimming Testing Therapeutic Intervention base cell motility ciliopathy extracellular gene function insight interest mutant neuronal cell body novel organelle movement particle positional cloning public health relevance response seven-transmembrane G-protein-coupled receptor transgene expression

项目摘要

DESCRIPTION (provided by applicant): Cilia are microtubule-based organelles that protrude from the surface of most mammalian cells for functions ranging from regulating body symmetry to sensory functions. Abnormalities in formation and maintenance of cilia often have variable pathologic consequences due to the near-ubiquity of these organelles. The structure and assembly of cilia are highly conserved and are readily studied in the motile flagella of the unicellular green alga Chlamydomonas reinhardtii. The length of flagella on these cells is highly responsive to the extracellular and intracellular environment. Understanding the signaling mechanisms involved in sensing abnormalities and responding with changes in length, as well as understanding the mechanisms involved in intrinsic length determination are critically important for identifying sources of cilia related pathology. To tackle this central question, I will first identify the function of uncharacterized signaling molecules that are unregulated during flagellar assembly including a GPCR and a lipase domain containing protein, FAP12. I will also investigate the complex interactions of known length-regulating proteins LF1p, LF2p, LF3p and LF4p to determine how they act with one another for tight control of flagellar length. Finally I will identify novel components in this pathway using an insertional mutagenesis screen for suppressors of a long flagella mutant. PUBLIC HEALTH RELEVANCE: Identifying and characterizing signaling molecules that can control the length of the nearly ubiquitous ciliary organelle will give us significant insights into the ciliopathies that result from abnormal cilium size. Specifically, testing the specific role of cilia length regulation complexes and identifying novel components in pathways regulating length will provide many new potential targets for therapeutic intervention in a wide range of ciliopathies. These ciliopathies include polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, hydrocephalus, retinal degeneration and many others.

描述（由申请人提供）：纤毛是基于微管的细胞器，从大多数哺乳动物细胞的表面突出，具有从调节身体对称性到感觉功能等多种功能。由于这些细胞器几乎无处不在，纤毛形成和维持的异常通常会产生不同的病理后果。纤毛的结构和组装高度保守，很容易在单细胞绿藻莱茵衣藻的活动鞭毛中进行研究。这些细胞上鞭毛的长度对细胞外和细胞内环境高度敏感。了解感知异常和响应长度变化所涉及的信号机制，以及了解固有长度确定所涉及的机制对于识别纤毛相关病理学的来源至关重要。为了解决这个核心问题，我将首先确定在鞭毛组装过程中不受调控的未表征信号分子的功能，包括 GPCR 和含有脂肪酶结构域的蛋白质 FAP12。我还将研究已知长度调节蛋白 LF1p、LF2p、LF3p 和 LF4p 的复杂相互作用，以确定它们如何相互作用以严格控制鞭毛长度。最后，我将使用插入诱变筛选长鞭毛突变体的抑制子来鉴定该途径中的新成分。公共健康相关性：识别和表征可以控制几乎无处不在的纤毛细胞器长度的信号分子将使我们对纤毛尺寸异常引起的纤毛病有重要的了解。具体来说，测试纤毛长度调节复合物的具体作用并识别长度调节途径中的新成分将为各种纤毛病的治疗干预提供许多新的潜在靶点。这些纤毛病包括多囊肾病、肾痨、Bardet-Biedl 综合征、脑积水、视网膜变性等。