Mechanisms generating ciliary structural diversity in C. elegans

线虫纤毛结构多样性的产生机制

• 批准号: 8118896
• 负责人: Anique Julienne Olivier-Mason
• 金额: $ 2.81万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118896
• 关键词: Affect; Afferent Neurons; Animals; Anosmia; Biological Models; Caenorhabditis elegans; Cells; Cilia; Defect; Disease; Ear; Exhibits; Functional disorder; Generations; Genetic; Goals; Hearing; Hearing problem; Homologous Gene; Human; Image; Kinocilium; Labyrinth; Lead; Maintenance; Mammalian Cell; Modeling; Morphology; Mutate; Mutation; Myosin ATPase; Nematoda; Neurons; Process; Proteomics; Regulation; Research; Role; Sensory; Smell Perception; Stereocilium; Structure; Syndrome; Usher Syndrome; Work; base; cell type; hearing impairment; in vivo; mutant; protein transport; public health relevance; research study; response; sensor

DESCRIPTION (provided by applicant): Primary cilia are now believed to be present in all mammalian cell types and act as environmental sensors. Generally, these cilia exhibit relatively simple structures. However, sensory cell types such as the kinocilia in the ear and olfactory sensory cilia exhibit highly specialized cilia structures that are essential for their specialized sensory functions. Although much is now known about how primary cilia are formed, very little is understood about the processes of building and maintaining specialized cilia. Loss of kinocilia or olfactory cilia function result in hearing loss and anosmia. Thus, understanding how these specialized cilia form and function is essential for a complete understanding of how animals smell and hear. C. elegans is an excellent model system in which to study the mechanisms of specialized cilia formation. Several chemosensory neuron types in C. elegans exhibit highly specialized cilia, which are essential for their sensory functions. The goal of this research is to define the genetic mechanisms required for the generation of specialized chemosensory cilia types. Using a proteomics-based approach, an unconventional myosin HUM-4 was identified as a candidate ciliary molecule. Mutations in hum-4 lead to ciliary defects specifically in an olfactory neuron type. Unconventional myosins have previously been implicated in maintenance of both kinocilia and stereocilia structures in the inner ear, and are mutated in hearing disorder syndromes such as Usher syndrome. The goal of this proposal is to investigate the functions of HUM-4 in the generation of specialized olfactory cilia morphology in the C. elegans model system. These cilia structures are essential for neuron-specific chemosensory responses so how sensory neurons are specialized for their unique functions will also be described. The proposed specific aims are: 1. Characterization of the role of the HUM-4 unconventional myosin in the regulation of ciliary morphology. 2. Elucidation of the mechanism by which the HUM-4 unconventional myosin regulates AWB ciliary morphology. PUBLIC HEALTH RELEVANCE: A thorough understanding of these mechanisms is important for a complete understanding of how humans hear and smell. This work will lead to a better understanding of how specialized cilia are formed, and how defects in cilia structure lead to sensory dysfunction.

描述(申请人提供)：初级纤毛现在被认为存在于所有哺乳动物细胞类型中，并充当环境传感器。一般来说，这些纤毛表现出相对简单的结构。然而，感觉细胞类型，如耳中的动纤毛和嗅觉纤毛，表现出高度专门化的纤毛结构，这对其专门化的感觉功能是必不可少的。虽然现在对初级纤毛是如何形成的了解很多，但对建立和维持特殊纤毛的过程了解很少。动纤毛或嗅觉纤毛功能的丧失会导致听力损失和嗅觉丧失。因此，了解这些特殊的纤毛是如何形成和功能的，对于全面了解动物如何闻和听是至关重要的。线虫是研究特化纤毛形成机制的一个很好的模型系统。线虫的几种化学感觉神经元类型显示出高度专门化的纤毛，这对它们的感觉功能是必不可少的。这项研究的目的是确定产生特殊的化学感觉纤毛类型所需的遗传机制。利用蛋白质组学的方法，一个非传统的肌球蛋白HUM-4被确定为一个候选的纤毛分子。Hum-4的突变会导致纤毛缺陷，特别是在一种嗅神经元型。非传统肌球蛋白此前被认为与维持内耳动纤毛和体纤毛结构有关，并在听力障碍综合征(如Usher综合征)中发生突变。这项建议的目的是研究hum-4在线虫模型系统中产生特殊的嗅觉纤毛形态中的功能。这些纤毛结构对于神经元特异性的化学感觉反应是必不可少的，因此感觉神经元是如何因其独特的功能而专门化的也将被描述。提出的具体目标是：1.表征hum-4非常规肌球蛋白在纤毛形态调节中的作用。2.阐明hum-4非常规肌球蛋白调控AWB纤毛形态的机制。 与公共卫生相关：彻底了解这些机制对于全面了解人类的听觉和嗅觉非常重要。这项工作将有助于更好地理解特殊纤毛是如何形成的，以及纤毛结构缺陷是如何导致感觉功能障碍的。