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）：本提案的长期目标是阐明嗅觉上皮（OE）细胞上纤毛在嗅觉功能调节和维持中的作用及其在纤毛相关疾病中的改变。嗅觉功能障碍在普通人群中很常见，仅在美国就影响了至少250万人。在至少20%的病例中，化学感觉障碍的病因无法确定。最近，我们是第一个证明嗅觉功能障碍作为一类新兴的人类遗传性疾病的临床表现之一，称为纤毛病。令人惊讶的是，虽然许多纤毛的功能据报道发生在OE和纤毛丰富的OSN，我们有一个不完整的理解纤毛在这个感觉组织中的作用。本申请中的新数据表明，水平基底细胞（HBC）具有纤毛（以前认为仅存在于OE中的嗅觉感觉神经元上），可以调节嗅觉干细胞的增殖或分化。因此，调查纤毛在OE中可能的多效性作用是必要的。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，但患者尚未获得治愈性治疗。最近，我们报道，气味检测可以恢复到动物的基因编码的纤毛蛋白IFFT 88，导致纤毛的损失分化的嗅觉感觉神经元（OSN）（参考）的亚型突变。这表明，异位基因在体内传递可能提供一个可行的方法来治疗嗅觉功能障碍引起的纤毛病变。我们假设，纤毛病变等位基因和纤毛基因的损失影响OSN和HBCS的功能，以减少嗅觉功能，这可以通过异位，腺病毒基因表达在体内治疗拯救。因此，我们将测试以下具体目的：（1）阐明纤毛从嗅觉感觉神经元损失的影响和在体内异位腺病毒基因递送后的功能拯救的程度;（2）确定纤毛损失引起的感觉恶化对嗅球组织和功能及其恢复后的可塑性的影响;（3）确定纤毛对HBC增殖和分化的调节在HBC中的必要性。 这项工作的成功完成无疑将为我们提供关于人类感觉知觉疾病发病机制的重要新信息，并为人类治疗的发展铺平道路，其中不存在对纤毛疾病的治愈性疗法。