Olfactory Signaling, Cilia, and Sensory Disorders

描述(申请人提供)：本提案的长期目标是阐明嗅觉上皮(OE)细胞纤毛在调节和维持嗅觉功能中的作用及其在纤毛相关疾病中的变化。嗅觉障碍在普通人群中很常见，仅在美国就有至少250万人受到影响。在至少20%的病例中，无法确定化学感觉障碍的病因。最近，我们是第一批证明嗅觉障碍是一种新兴的人类遗传性疾病的临床表现的人之一，被称为纤毛疾病。令人惊讶的是，虽然许多被归因于纤毛的功能被报道存在于OE中，并且OSNs上的纤毛丰富，但我们对纤毛在这一感觉组织中的作用还没有完全的了解。在这一应用中的新数据显示，水平基底细胞(HBC)具有纤毛(以前认为存在于OE中仅存在于嗅觉神经元上)，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，尽管在确定纤毛疾病的基因方面取得了重大进展，但患者尚未获得根治疗法。最近，我们报道了编码纤毛蛋白IFT88的基因发生亚型突变，导致分化的嗅觉神经元(OSNs)纤毛丢失的动物可以恢复气味检测。这表明，体内异位基因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缺失影响OSNs和HBCs的功能，从而降低嗅觉功能，这可以通过体内异位的腺病毒基因表达来治疗。因此，我们将测试以下具体目标：(1)阐明异位腺病毒基因导入后嗅觉感觉神经元纤毛丢失的影响和功能挽救的程度；(2)确定纤毛丢失对嗅球组织和功能及其修复后可塑性的影响；(3)确定纤毛对HBC增殖和分化调节的必要性。 发展、成熟和受伤的OE。这项工作的成功完成无疑将为我们提供关于人类感觉性疾病发病机制的重要新信息，并为开发针对纤毛疾病的治疗方法铺平道路。

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.