Regeneration and regrowth of sensory cilia via non-canonical mechanisms

描述（由申请人提供）：初级纤毛是基于微管的感觉细胞器，目前已知存在于人类和其他后生动物的几乎所有细胞类型上。纤毛是信号分子的房子，需要准确地感知和识别环境刺激。纤毛对于外周化学感觉神经元、机械感觉神经元和光感觉神经元的感觉功能特别重要。例如，嗅觉信号蛋白集中在嗅觉感觉神经元树突状突起发出的纤毛中。嗅觉纤毛的破坏导致嗅觉丧失。类似地，内耳中动纤毛的丧失导致静纤毛束组织的缺陷，从而导致听力异常。纤毛功能障碍是一系列统称为纤毛病的病症和疾病的基础。 纤毛发生机制在物种间是高度保守的，从模式生物如C。elegans和Chlamydia在定义纤毛结构和功能所需的分子和机制方面起了重要作用。C.秀丽线虫是有纤毛的，并且与它们的脊椎动物对应物一样，这些纤毛含有信号分子并且对于感觉传导是必需的。所有纤毛都是由鞭毛内运输或IFT的高度保守过程形成的; IFT基因功能的丧失导致严重的纤毛结构缺陷。我们发现了一个令人惊讶的现象，即在C.缺乏IFT基因功能的线虫。这些过程类似于真正的纤毛，因为它们容纳纤毛蛋白并部分恢复感觉神经元的化学感觉功能。我们推测衰老通过部分非经典的纤毛发生机制诱导C.优雅这个探索性的R21提案的总体目标是进一步研究这个以前未描述的再生过程的机制。具体目的是：1）描述IFT突变体中再生纤毛样结构的结构和功能。在这个目标中提出的实验将调查在何种程度上的结构和功能的再生纤毛样结构在老年IFT突变体类似的纤毛存在于年龄匹配的野生型动物。2)研究老年IFT突变体中纤毛样结构再生长所需的机制。在这个目标中提出的实验将研究在衰老动物中触发纤毛样结构再生长的机制，以及确定介导再生长的分子和途径。 从这项工作的结果将提供框架的设计，未来的实验旨在进一步表征这种以前未描述的现象，年龄调节的纤毛再生的核心IFT基因功能的情况下。由于纤毛发生机制是非常保守的跨门，我们希望我们的研究结果将有重大影响，我们的纤毛生成和维护的知识，并可能提出新的途径和策略，以针对纤毛病变和感觉神经元功能障碍。

DESCRIPTION (provided by applicant): Primary cilia are microtubule-based sensory organelles that are now known to be present on nearly all cell types in humans and other metazoans. Cilia house signaling molecules and are required to accurately sense and transduce environmental stimuli. Cilia are particularly critical for the sensory functions of peripheral chem-, mechano- and photo-sensory neurons. For instance, olfactory signaling proteins are concentrated in the cilia that emanate from the dendritic knob of olfactory sensory neurons. Disruption of olfactory cilia results in anosmia. Similarly, loss of kinocilia in the inner ear reslts in defects in the organization of the stereocilia bundle leading to hearing anomalies. Ciliary dysfunction underlies a range of disorders and diseases collectively referred to as ciliopathies. Ciliogenic mechanisms are highly conserved across species, and insights from model organisms such as C. elegans and Chlamydomonas have been instrumental in defining molecules and mechanisms required for cilia structure and function. A subset of sensory neurons in C. elegans is ciliated and as in their vertebrate counterparts, these cilia contain signaling molecules and are essential for sensory transduction. All cilia are formed by the highly conserved process of intraflagellar transport or IFT; loss of IFT gene function results in severe ciliary structural defects. We made the surprising observation that cilia-like processes regenerate and regrow upon aging in a subset of chemosensory neurons in C. elegans lacking IFT gene function. These processes resemble bona fide cilia since they house ciliary proteins and partly restore chemosensory functions to the sensory neurons. We hypothesize that aging induces ciliary regrowth or regeneration via partly non- canonical ciliogenic mechanisms in C. elegans. The overall goal of this exploratory R21 proposal is to further investigate the mechanisms of this previously undescribed regeneration process. The Specific Aims are to: 1) Describe the structure and function of regenerated cilia-like structures in IFT mutants. Experiments proposed in this aim will investigate the extent to which the structure and function of the regenerated cilia-like structures in aged IFT mutants resemble those of cilia present in age-matched wild-type animals. 2) Investigate the mechanisms required for regrowth of cilia-like structures in aged IFT mutants. Experiments proposed in this aim will investigate the mechanisms by which regrowth of the cilia-like structures is triggered in aging animals, as well as identify the molecules and pathways which mediate the regrowth. Results from this work will provide the framework for the design of future experiments aimed at further characterizing this previously undescribed phenomenon of age-regulated ciliary regrowth in the absence of core IFT gene function. Since ciliogenic mechanisms are remarkably conserved across phyla, we expect that our findings will have major implications on our knowledge of cilia generation and maintenance, and may suggest new avenues and strategies to target ciliopathies and sensory neuron dysfunction.