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）：本研究的长期目标是了解纤毛和鞭毛的结构、组装和功能，以及它们在人类健康中的作用。这些研究利用衣原体和小鼠作为模式生物，并侧重于纤毛生物中高度保守的过程和蛋白质。将采取遗传、生物化学和细胞生物学方法相结合的方法。研究中的一个过程是鞭毛内转运（IFT），这是几乎所有纤毛和鞭毛的组装和维持所必需的。IFT涉及到粒子向鞭毛尖端和返回的运动。这些粒子包含至少16个不同的亚基，但几乎不知道单个亚基的功能。研究将表征两种高度保守的IFT颗粒蛋白，IFT 46和IFT 20中缺陷的衣原体无效突变体，以测试IFT 46参与外动力蛋白臂运输到鞭毛中以及IFT 20参与膜蛋白向鞭毛的递送的假设。另一个正在研究的过程是纤毛和鞭毛运动的机制。一种蛋白质最近牵连在这个过程中是hydin，一个组成部分的中央对（CP）的微管在衣原体鞭毛轴丝。Hydin似乎在控制动力蛋白臂活性的CP/放射状辐条信号通路中起作用。将进行实验，以确定蛋白质与乙内脂相互作用的CP和径向辐条。在小鼠和可能在人类中，Hydin缺陷导致脑积水，这是脑室内脑脊液的致命积聚。研究将使用Hydin缺陷的小鼠来确定Hydin是否也是哺乳动物中的CP蛋白，以及它是否对大脑和气道中的纤毛运动很重要。在相关的研究中，将进行衣原体CP蛋白的全球分析，以填补我们对这一重要结构的认识中的巨大空白，并促进对hydin和CP/径向辐条相互作用的研究。另一个正在研究的重要疾病蛋白是肾囊蛋白-4。肾囊蛋白-4的缺陷导致人类囊性肾病和视网膜变性。它被认为是纤毛过渡区的蛋白质，但对其功能一无所知。一个衣原体突变体缺乏肾囊蛋白-4的特点，以了解更多关于这种蛋白质的特定位置和功能的过渡区。研究中的过程和蛋白质的缺陷会导致人类和脊椎动物模式生物的疾病。这项研究将为纤毛和鞭毛在囊性肾病、视网膜变性、原发性纤毛运动障碍、男性不育和脑积水中的作用提供新的信息。