Flagellar Motility and Assemlby

鞭毛运动和组装

• 批准号: 7931462
• 负责人: George B Witman
• 金额: $ 9.19万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931462
• 关键词: Address; Animal Model; Back; Biochemical; Biological; Brain; Cell surface; Cells; Cerebral Ventricles; Cerebrospinal Fluid; Chlamydomonas; Cilia; Complex; Cystic Kidney Diseases; Cystic kidney; Defect; Disease; Dynein ATPase; Etiology; Flagella; Foundations; Generations; Genetic; Goals; Head; Health; Human; Hydrocephalus; Individual; Investigation; Knowledge; Learning; Location; Maintenance; Male Infertility; Mammals; Membrane Proteins; Microtubules; Molecular; Molecular Genetics; Movement; Mus; Organism; Primary Ciliary Dyskinesias; Process; Proteins; Proteomics; Radial; Research; Research Personnel; Retinal Degeneration; Role; Signal Pathway; Structure; Testing; Tissues; Upper arm; base; cell motility; complement C2b; fluid flow; human TYRP1 protein; kinetosome; mutant; particle; programs; research study

DESCRIPTION (provided by applicant): The long-term goals of this research are to understand the structure, assembly, and function of cilia and flagella, and their roles in human health. The studies are utilizing Chlamydomonas and mice as model organisms, and are focused on processes and proteins that are highly conserved among ciliated organisms. A combination of genetic, biochemical and cell biological approaches will be taken. One process under investigation is intraflagellar transport (IFT), which is necessary for the assembly and maintenance of almost all cilia and flagella. I FT involves the movement of particles to the tip of the flagellum and back. These particles contain at least 16 different subunits, but almost nothing is known about the functions of the individual subunits. Studies will characterize Chlamydomonas null mutants defective in two highly conserved IFT-particle proteins, IFT46 and IFT20, to test the hypotheses that IFT46 is involved in transport of the outer dynein arms into the flagellum, and that IFT20 is involved in delivery of membrane proteins to the flagellum. Another process being studied is the mechanism of ciliary and flagellar movement. One protein recently implicated in this process is hydin, a component of the central pair (CP) of microtubules in the Chlamydomonas flagellar axoneme. Hydin appears to have a role in the CP/radial spoke signaling pathway that controls dynein arm activity. Experiments will be carried out to identify the proteins with which hydin interacts in both the CP and the radial spokes. In the mouse and possibly in humans, Hydin defects cause hydrocephalus, which is the lethal accumulation of cerebrospinal fluid in the ventricles of the brain. Studies will use mice defective in Hydin to determine if Hydin also is a CP protein in mammals, and if it is important for ciliary motility in the brain and airway. In related studies, a global analysis of Chlamydomonas CP proteins will be carried out to fill a large gap in our knowldedge of this important structure, and to facilitate studies of hydin and of CP/radial spoke interaction. Another important disease protein being investigated is nephrocystin-4. Defects in Nephrocystin-4 cause cystic kidney disease and retinal degeneration in humans. It is believed to be a protein of the ciliary transition region, but nothing is known about its function. A Chlamydomonas mutant lacking nephrocystin-4 will be characterized to learn more about this protein's specific location and function in the transition region. Defects in the processes and proteins under investigation cause disease in humans and vertebrate model organisms. The research will provide new information on the role of cilia and flagella in cystic kidney disease, retinal degeneration, primary ciliary dyskinesia, male infertility, and hydrocephalus.

描述（由申请人提供）：这项研究的长期目标是了解西里亚和鞭毛的结构，组装和功能及其在人类健康中的作用。这些研究将衣原体和小鼠用作模型生物，并专注于在纤毛生物中高度保守的过程和蛋白质。将采用遗传，生化和细胞生物学方法的结合。正在研究的一个过程是flagellar运输（IFT），这对于几乎所有纤毛和鞭毛的组装和维护都是必需的。 I FT涉及颗粒向鞭毛和背部的尖端的运动。这些粒子至少包含16个不同的亚基，但几乎没有任何一个亚基的功能知道。研究将表征两种高度保守的IFT粒子蛋白IFT46和IFT20中有缺陷的衣原体无效突变体，以测试假设IFT46参与外部动力蛋白臂进入鞭毛的转运，并且IFT20参与膜蛋白向鞭毛的递送。研究的另一个过程是睫状和鞭毛运动的机制。最近与此过程有关的一种蛋白质是Hydin，Hydin是衣原体鞭毛轴突中微管中心对（CP）的组成部分。 Hydin似乎在控制动力蛋白ARM活性的CP/radial辐条信号通路中起作用。将进行实验，以鉴定hydin在CP和径向辐条中相互作用的蛋白质。在小鼠中，可能在人类中，海丁缺陷引起脑积水，这是脑室脑室脑在大脑心室中的致命积累。研究将使用在hydin中有缺陷的小鼠来确定海丁是否也是哺乳动物中的CP蛋白，并且它对于大脑和气道中的睫状运动是否很重要。在相关研究中，将对衣原部CP蛋白进行全球分析，以填补我们对这一重要结构的知识范围的巨大空白，并促进Hydin和CP/Radial辐条相互作用的研究。正在研究的另一个重要疾病蛋白是肾上腺囊蛋白4。肾环胞菌4的缺陷引起人类囊性肾脏疾病和视网膜变性。它被认为是睫状过渡区域的蛋白质，但对其功能一无所知。缺乏肾环胞固醇4的衣原体突变体的特征是更多地了解该蛋白质在过渡区域中的特定位置和功能。研究过程中的缺陷和蛋白质的缺陷导致人类和脊椎动物模型生物的疾病。该研究将提供有关纤毛和鞭毛在囊性肾脏疾病，视网膜变性，原发性睫状运动障碍，男性不育症和脑积水中作用的新信息。