Olfactory Signaling, Cilia, and Sensory Disorders

描述（由申请人提供）：本提案的长期目标是阐明纤毛对嗅上皮细胞（OE）在嗅觉功能的调节和维持及其在纤毛相关疾病中的改变中的作用。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是一种新兴的人类遗传疾病的临床表现，称为纤毛病。令人惊讶的是，虽然据报道纤毛的许多功能发生在OE，并且纤毛在osn上大量存在，但我们对纤毛在这种感觉组织中的作用的了解并不完全。这项应用的新数据表明，水平基底细胞（hbc）具有纤毛（以前认为仅存在于OE的嗅觉感觉神经元上），可能调节嗅觉干细胞的增殖或分化。因此，研究纤毛在OE中可能的多效性作用是必要的。重要的是，尽管在确定潜在纤毛病的基因方面取得了重大进展，但治疗方法尚未对患者有效。最近，我们报道了纤毛蛋白IFT88编码基因的亚形态突变，导致分化嗅觉感觉神经元（OSNs）上的纤毛缺失，从而恢复动物的气味检测（参考文献）。这表明体内异位基因传递可能为治疗由纤毛病引起的嗅觉功能障碍提供了一种可行的方法。我们假设纤毛病等位基因和纤毛基因的缺失会影响OSNs和HBCS的功能，从而降低嗅觉功能，这可以通过体内异位腺病毒基因表达来治疗性地挽救。因此，我们将测试以下具体目的：(1)阐明异位腺病毒基因在体内传递后嗅觉感觉神经元纤毛丢失的影响和功能恢复的程度；(2)确定纤毛丢失引起的感觉退化对嗅球组织功能及其修复后可塑性的影响；(3)确立纤毛对肝癌细胞增殖分化调控的必要性

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.