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.
Although many of the causes of loss of smell have yet to be discovered, one known cause is a disruption of cilia, hair-like projections extending from neurons into the nasal cavity. Cilia contain proteins responsible for detecting odors, hence genetic diseases that disrupt the cilia have been tied to the loss of smell. The goal for this proposal is to better understand the function and mutations of cilia and to determine how to therapeutically treat such disorders.
|Green, Warren W; Uytingco, Cedric R; Ukhanov, Kirill et al. (2018) Peripheral Gene Therapeutic Rescue of an Olfactory Ciliopathy Restores Sensory Input, Axonal Pathfinding, and Odor-Guided Behavior. J Neurosci 38:7462-7475|
|Uytingco, Cedric R; Green, Warren W; Martens, Jeffrey R (2018) Olfactory loss and dysfunction in ciliopathies: Molecular mechanisms and potential therapies. Curr Med Chem :|
|Williams, Corey L; Uytingco, Cedric R; Green, Warren W et al. (2017) Gene Therapeutic Reversal of Peripheral Olfactory Impairment in Bardet-Biedl Syndrome. Mol Ther 25:904-916|
|Chen, Kevin S; McIntyre, Jeremy C; Lieberman, Andrew P et al. (2016) Human spinal autografts of olfactory epithelial stem cells recapitulate donor site histology, maintaining proliferative and differentiation capacity many years after transplantation. Acta Neuropathol 131:639-40|
|Joiner, Ariell M; Green, Warren W; McIntyre, Jeremy C et al. (2015) Primary Cilia on Horizontal Basal Cells Regulate Regeneration of the Olfactory Epithelium. J Neurosci 35:13761-72|
|McIntyre, Jeremy C; Joiner, Ariell M; Zhang, Lian et al. (2015) SUMOylation regulates ciliary localization of olfactory signaling proteins. J Cell Sci 128:1934-45|
|Williams, Corey L; McIntyre, Jeremy C; Norris, Stephen R et al. (2014) Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia. Nat Commun 5:5813|
|McIntyre, Jeremy C; Williams, Corey L; Martens, Jeffrey R (2013) Smelling the roses and seeing the light: gene therapy for ciliopathies. Trends Biotechnol 31:355-63|
|Rachel, Rivka A; May-Simera, Helen L; Veleri, Shobi et al. (2012) Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis. J Clin Invest 122:1233-45|
|McIntyre, Jeremy C; Davis, Erica E; Joiner, Ariell et al. (2012) Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat Med 18:1423-8|
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