2014 — 2018 |
Martens, Jeffrey |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Olfactory Signaling, Cilia, and Sensory Disorders
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.
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0.915 |
2021 |
Martens, Jeffrey |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Maintece and Disassembly of Olfactory Cilia
TITLE: Maintenance and Disassembly of Olfactory Cilia The long-term goal of this project is to determine the role of cilia in the regulation and maintenance of olfactory function and their alterations in cilia-related disorders. Olfactory dysfunction is common, affecting at least 16 million people in the U.S. alone. Our lab and others have found olfactory dysfunction to be a clinical manifestation of a class of human genetic disorders termed ciliopathies. Bardet-Biedl syndrome (BBS) is one such disorder, in which the altered cilia morphology of olfactory sensory neurons (OSNs) renders the cells unresponsive to odors. Despite the identification of numerous genes underlying ciliopathies, curative therapies (including for olfactory dysfunctions) are not yet available to patients. We reported that gene replacement to restore cilia and hence sensory input in a limited number of differentiated OSNs was sufficient to rescue peripheral odor responses in mouse models of a subset of ciliopathies. However, to better understand cilia biology in the olfactory system and advance potential therapies, we must define the cellular mechanisms underlying olfactory penetrance of ciliopathies. We must also determine whether these mechanisms are conserved across different ciliopathies and might thus be amenable to the same therapeutic strategies. OSN cilia compartmentalize all of necessary signaling machinery for odor detection and even though OSN cilia can be lost in both physiological and pathological conditions, the cellular mechanisms that maintain the integrity of this essential OSN cell compartment remain poorly understood. Cilia in other cells and organisms contain a multiprotein complex at its base, termed the transition zone (TZ), that functions as a regulatory gate to control the unique protein and lipid composition of cilia. Surprisingly little is known about the TZ in OSNs. This grant application will elucidate the composition and subcellular organization of the OSN cilia TZ and how aberrant protein and lipid translocation into cilia contributes to the disassembly of cilia. Our preliminary data suggest that alterations in intracellular Ca2+ contribute to cilia disassembly by disrupting TZ components. We hypothesize that sustained elevations of intracellular Ca2+ result in TZ remodeling of OSN cilia that is permissive for changes in cilia membrane lipid distribution and actin infiltration, both of which are necessary for cilia disassembly in ciliopathies. Therefore, we propose the following Specific Aims: (1) Determine the composition and organization of the OSN cilia TZ and alterations accompanying disassembly in ciliopathies; (2) Determine the effects of elevated intracellular Ca2+ on OSN cilia disassembly; (3) Determine the role of membrane PIP2 redistribution and F-actin infiltration in cellular mechanisms of OSN cilia disassembly. Successful completion of this work will provide critical new insights into the pathogenesis of human sensory perception diseases and is a necessary step for the development of treatments for congenital anosmia and related olfactory dysfunctions that result from ciliopathy.
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0.915 |