Olfactory Signaling, Cilia, and Sensory Disorders

嗅觉信号、纤毛和感觉障碍

• 批准号: 8631898
• 负责人: Jeffrey Martens
• 金额: $ 45.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-17 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631898
• 关键词: Affect; Afferent Neurons; Age; Alleles; Animals; Basal Cell; Behavior; Biochemical; Cell Death; Cell Proliferation; Cells; Cilia; Clinical; Data; Defect; Detection; Development; Disease; Etiology; Functional disorder; Gene Delivery; Gene Expression; Gene Mutation; General Population; Genes; Genetic; Goals; Hair; Hereditary Disease; Human; Human Genetics; Investigation; Maintenance; Maps; Measures; Modeling; Molecular; Mutation; Nasal cavity; Neurons; Odors; Olfactory Epithelium; Pathogenesis; Patients; Pattern; Perception; Phenotype; Population; Process; Property; Proteins; Recovery; Regulation; Reporting; Role; Sensory; Sensory Deprivation; Sensory Disorders; Signal Transduction; Signaling Protein; Smell Perception; Stem cells; Structure; Techniques; Testing; Time; Tissues; Work; axon guidance; ciliopathy; fluorescence imaging; imaging modality; in vivo; injured; loss of function; neurochemistry; neurogenesis; olfactory bulb; public health relevance; regenerative; response to injury; restoration; self-renewal; stem; therapy development

TITLE: Olfactory Signaling, Cilia, and Sensory Disorders The long-term goal of this proposal is to elucidate the role of cilia on cells of the olfactory epithelium (OE) in the regulation and maintenance of olfactory function and their alterations in cilia-related disorders. Olfactory dysfunction in the general population is frequent, affecting at least 2.5 million people in the U.S. alone. In at least 20% of the cases the etiology of the chemosensory disturbance cannot be identified. Recently, we were one of the first to demonstrate olfactory dysfunction as a clinical manifestation of an emerging class of human genetic disorders, termed ciliopathies. It is surprising that while many of the ascribed functions of cilia are reported to occur in the OE and cilia are abundant on OSNs, we have an incomplete understanding of the role of cilia in this sensory tissue. New data in this application show that horizontal basal cells (HBCs) possess cilia (previously thought to exist in the OE only on olfactory sensory neurons) that may regulate proliferation or differentiation of olfactory stem cells. Therefore, investigation into the possible pleotropic roles of cilia in the OE is necessary. Importantly, despite significant progress identifying the genes underlying ciliopathies, curative therapies are not yet available to patients. Recently, we reported that odor detection can be restored to animals with a hypomorphic mutation in the gene encoding for the ciliary protein IFT88 that results in the loss of cilia on differentiated olfactory sensory neurons (OSNs)(ref). This suggests that ectopic gene delivery in vivo may provide a viable approach to treating olfactory dysfunction resulting from ciliopathies. We hypothesize that ciliopathy alleles and loss of cilia genes affect the function of both OSNs and HBCS to reduce olfactory function, which can be therapeutically rescued by ectopic, adenoviral-gene expression in vivo. Therefore, we will test the following Specific Aims: (1) Elucidate the effects of cilia loss from olfactory sensory neurons and the extent of functional rescue following ectopic adenoviral gene delivery in vivo; (2) Determine the effects of sensory depravation by cilia loss on olfactory bulb organization and function and its plasticity following restoration; (3) Establish the necessity of cilia for the regulation of HBC proliferation and differentiation in the developing, mature, and injured OE. Successful completion of this work will undoubtedly provide us important new information regarding the pathogenesis of human sensory perception diseases and paves the way for the development of treatments in humans, where no curative therapies for ciliopathic disease exist.

标题：嗅觉信号，纤毛和感觉障碍 这项建议的长期目标是阐明纤毛对嗅觉上皮细胞（OE）在嗅觉系统中的作用。 调节和维持嗅觉功能及其在纤毛相关疾病中的改变。嗅觉 一般人群中的功能障碍是常见的，仅在美国就影响至少250万人。中 至少20%的病例不能确定化学感觉障碍的病因。最近，我们在 最早证明嗅觉功能障碍是一类新兴的人类疾病的临床表现之一， 遗传性疾病，称为纤毛病。令人惊讶的是，虽然纤毛的许多功能被认为是 据报道，发生在OE和纤毛丰富的OSN，我们有一个不完整的了解的作用， 感觉组织中的纤毛。新的数据表明，水平基底细胞（HBCs）具有纤毛 （以前认为只存在于OE上的嗅觉感觉神经元），可能调节增殖或 嗅觉干细胞的分化因此，研究纤毛在细胞中可能的多效性作用， OE是必要的。重要的是，尽管在确定纤毛病变相关基因方面取得了重大进展， 患者尚不能获得治疗。最近，我们报道了气味检测可以恢复到 在编码纤毛蛋白IFFT 88的基因中具有亚型突变的动物，该亚型突变导致丧失 纤毛对分化的嗅觉感觉神经元（OSN）的影响（参考文献）。这表明体内异位基因传递 可以提供一种治疗由纤毛病引起的嗅觉功能障碍的可行方法。我们假设 纤毛病变等位基因和纤毛基因的缺失影响OSN和HBCS降低嗅觉的功能， 功能，其可以通过异位腺病毒基因在体内表达来治疗性地挽救。所以我们 将测试以下具体目标：（1）阐明嗅觉感觉神经元纤毛损失的影响， 体内异位腺病毒基因递送后功能拯救的程度;（2）确定 纤毛缺失对嗅球组织和功能的影响及其可塑性 （3）确定纤毛对HBC增殖和分化的调节的必要性。 成功完成这项工作无疑将为我们提供重要的 关于人类感觉知觉疾病发病机制的新信息，并为 开发人类治疗方法，其中不存在针对纤毛疾病的治愈性疗法。