Olfactory Signaling, Cilia, and Sensory Disorders

嗅觉信号、纤毛和感觉障碍

• 批准号: 9246523
• 负责人: Jeffrey Martens
• 金额: $ 43.92万
• 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/9246523
• 关键词: Affect; Age; Alleles; Animals; Basal Cell; Behavior; Biochemical; Cell Death; Cell Differentiation process; Cell Proliferation; Cells; Cilia; Clinical; DNA Sequence Alteration; Data; Defect; Detection; Development; Disease; Electrophysiology (science); Etiology; Functional disorder; Gene Delivery; Gene Expression; General Population; Genes; Genetic; Goals; Hair; Hereditary Disease; Human; Human Genetics; Investigation; Loss of Heterozygosity; Maintenance; Maps; Measures; Modeling; Molecular; Mutation; Nasal cavity; Neurons; Odors; Olfactory Epithelium; Pathogenesis; Patients; Pattern; Perception; Phenotype; Population; Property; Proteins; Recovery; Regulation; Reporting; Role; Sensory; Sensory Deprivation; Sensory Disorders; Signal Transduction; Signaling Protein; Smell Perception; Stem cells; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Work; axon guidance; ciliopathy; curative treatments; fluorescence imaging; imaging modality; in vivo; injured; loss of function; neurochemistry; neurogenesis; olfactory bulb; olfactory sensory neurons; public health relevance; regenerative; response to injury; restoration; self-renewal; stem; therapy development

DESCRIPTION (provided by applicant): 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 leas 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 role 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.

描述（由申请人提供）：该提案的长期目标是阐明纤毛对嗅觉上皮（OE）细胞在嗅觉功能的调节和维持中的作用及其在纤毛相关疾病中的改变。普通民众的嗅觉功能障碍经常出现，仅在美国就会影响至少250万人。在LEAS中，20％的病例无法识别出化学感应障碍的病因。最近，我们是最早证明嗅觉功能障碍作为新兴类人遗传疾病的临床表现的人之一，称为纤毛病。令人惊讶的是，尽管据报道在OE中出现了许多CILIA的归因功能，而Cilia在OSN上很丰富，但我们对Cilia在该感觉组织中的作用有不完全理解。本应用程序中的新数据表明，水平基底细胞（HBC）具有纤毛（以前认为仅在OE中仅存在于嗅觉感觉神经元中），可能会调节嗅觉干细胞的增殖或分化。因此，必须调查纤毛在OE中可能的主体作用。重要的是，尽管鉴定出基因基因纤毛病的基因，但患者尚无治愈疗法。最近，我们报告说，在编码纤毛蛋白IFT88的基因中，可以将气味检测恢复为具有型肌肉突变的动物，从而导致在分化的嗅觉性感觉神经元（OSN）上导致纤毛损失（参考）。这表明体内的异位基因递送可以提供一种可行的方法来治疗纤毛病变引起的嗅觉功能障碍。我们假设纤毛病等位基因和纤毛基因的丧失会影响OSN和HBC的功能减少嗅觉功能，这可以通过体内异位，腺病毒 - 基因表达来治疗。因此，我们将测试以下特定目的：（1）阐明嗅觉感觉神经元损失的影响以及在体内异位腺病毒基因递送后的功能救援程度； （2）确定纤毛丧失对嗅球的组织和功能及其恢复后的可塑性的影响； （3确定纤毛的必要性，以调节HBC增殖和分化 开发，成熟和受伤的OE。这项工作的成功完成无疑将为我们提供有关人类感觉知觉疾病的发病机理的重要新信息，并为人类治疗的发展铺平了道路，在那里不存在治疗纤毛性疾病的治疗方法。