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在嗅觉上皮(OE)细胞中的作用。 纤毛相关性疾病中嗅觉功能的调节和维持及其变化。嗅觉 普通人群中的功能障碍很常见，仅在美国就有至少250万人受到影响。在At 至少有20%的病例无法确定化学感觉障碍的病因。最近，我们正在 第一个将嗅觉障碍作为新兴人类临床表现的人之一 遗传性疾病，称为纤毛病。令人惊讶的是，虽然纤毛的许多被认为的功能是 据报道，发生在OE和纤毛上的OSNs丰富，我们对其作用还没有完全了解 感觉组织中的纤毛。这一应用中的新数据表明，水平基底细胞(HBC)具有纤毛 (以前被认为只存在于OE中的嗅觉感觉神经元)，可能调节增殖或 嗅觉干细胞的分化。因此，对纤毛可能的多效性作用的研究 OE是必要的。重要的是，尽管识别纤毛疾病的基因取得了重大进展，但治愈性 目前还没有治疗方法提供给患者。最近，我们报道了气味检测可以恢复到 导致纤毛蛋白IFT88缺失的基因亚型突变的动物 纤毛对分化的嗅觉神经元(OSNs)的影响(参考文献)。这表明异位基因在体内的传递 可能为治疗纤毛疾病引起的嗅觉功能障碍提供一种可行的方法。我们假设 纤毛病变等位基因和纤毛基因的丢失影响OSNs和HbCs降低嗅觉的功能 功能，这可以通过体内异位的腺病毒基因表达而在治疗上挽救。因此，我们 将测试以下具体目标：(1)阐明嗅觉神经元纤毛丢失的影响和 异位腺病毒基因体内传递后功能挽救的程度；(2)确定 嗅球组织和功能纤毛缺失引起的感觉退化及其可塑性 (3)确定纤毛在调节HBC增殖和分化中的必要性。 发展、成熟和受伤的OE。这项工作的圆满完成无疑将为我们提供重要的 关于人类感觉性疾病发病机制的新信息，并为 在人类身上开发治疗方法，在那里没有针对纤毛疾病的根治疗法。