Regeneration and regrowth of sensory cilia via non-canonical mechanisms

通过非典型机制感觉纤毛的再生和再生长

• 批准号: 8573916
• 负责人: Piali Sengupta
• 金额: $ 20.19万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573916
• 关键词: Affect; Afferent Neurons; Age; Aging; Animal Model; Animals; Anosmia; Bypass; Caenorhabditis elegans; Cell physiology; Cells; Chemicals; Chlamydomonas; Cilia; Cilium Microtubule; Defect; Development; Disease; Erinaceidae; Exhibits; Functional disorder; Future; GTP-Binding Proteins; Generations; Genes; Goals; Hearing; Homeostasis; Housing; Human; Inner Hair Cells; Kinetics; Kinocilium; Knowledge; Labyrinth; Lead; Light; Maintenance; Mediating; Microtubules; Morphology; Motor; Natural regeneration; Nervous system structure; Neuraxis; Neurons; Olfactory Receptor Neurons; Organelles; Organism; Pathway interactions; Pattern; Peripheral; Photoreceptors; Process; Proteins; Rhodopsin; Sensory; Signal Transduction; Signaling Molecule; Signaling Protein; Stereocilium; Stimulus; Structure; Structure of ciliary processes; Transmission Electron Microscopy; Transport Process; Vertebrates; Work; aged; base; cell type; ciliopathy; cilium biogenesis; design; gene function; in vivo; insight; morphogens; mutant; neurogenesis; novel; olfactory receptor; public health relevance; research study; trafficking

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.

描述（由申请人提供）：原发性纤毛是基于微管的感觉细胞器，现在已知在人类和其他后生动物中几乎所有细胞类型上都存在。纤毛房屋信号分子，需要准确感知和传播环境刺激。纤毛对于外周化学，机械和光感神经元的感觉功能特别重要。例如，嗅觉信号蛋白集中在纤毛中，这些纤毛是从嗅觉感觉神经元的树突状旋钮中散发出来的。嗅觉纤毛的破坏会导致厌食。同样，内耳损失在立体束组织中的缺陷中导致听力异常。睫状功能障碍是一系列疾病和疾病的基础，共同称为纤毛病。 纤毛生成的机制在各种物种之间是高度保守的，秀丽隐杆线虫和衣原体等模型生物的见解对定义了纤毛结构和功能所需的分子和机制有助于。秀丽隐杆线虫中的感觉神经元的子集被纤毛纤毛，就像在其脊椎动物对应物中一样，这些纤毛包含信号分子，对于感觉转导至关重要。所有纤毛均由高度保守的氟法内运输或IFT形成。 IFT基因功能的丧失导致严重的睫状结构缺陷。我们做出了一个令人惊讶的观察，即在缺乏IFT基因功能的秀丽隐杆线虫中，类似纤毛的过程在衰老的一部分中衰老而再生。这些过程类似于真正的纤毛，因为它们容纳睫状蛋白并部分恢复了感觉神经元的化学感应函数。我们假设衰老会通过秀丽隐杆线虫中部分非典型的纤毛生成机制诱导纤毛再生或再生。该探索性R21提案的总体目标是进一步研究这种先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。在此目的中提出的实验将研究重生的IFT突变体中再生类似纤毛的结构的结构和功能类似于年龄匹配的野生型动物中存在的纤毛。 2）研究年龄IFT突变体中纤毛样结构再生所需的机制。在此目标中提出的实验将研究在衰老动物中触发类似纤毛的结构再生的机制，并识别介导这种再生的分子和途径。 这项工作的结果将为未来实验的设计提供框架，旨在进一步表征这种先前未描述的在没有核心IFT基因功能的睫状性再生的现象。由于纤毛生成机制在整个门中都非常保守，因此我们希望我们的发现将对我们对纤毛生成和维持的了解具有重大影响，并可能提出针对纤毛病和感觉神经元功能障碍的新途径和策略。