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Improving olfactory neuroplasticity through FAK/CNTF signaling

Award Number: R01DC020528
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Improving olfactory neuroplasticity through FAK/CNTF signaling - Project Summary Olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) are continuously replaced from basal stem cells and grow their axons to the olfactory bulb to maintain the sense of smell. Failure to reconstitute the OE after injury, infection or aging, causes olfactory dysfunction which is a safety and a quality of life issue. No treatments are available. Defining the signals that regulate olfactory neuroplasticity would reveal new therapeutic targets to improve olfactory deficits. Ciliary neurotrophic factor (CNTF) is highly expressed in horizontal basal cells (HBCs) and olfactory ensheathing cells (OECs), while the CNTFRα receptor is expressed in the neighboring neuronal progenitor globose basal cells (GBCs). We found that CNTF is suppressed by focal adhesion kinase (FAK) and that intranasal application of an FAK inhibitor promotes OE neurogenesis via CNTF. Importantly, FAK inhibitor further enhances CNTF expression caused by OE injury with methimazole. We will use genetic, pharmacological, and behavioral approaches in male and female mice to test the hypothesis that FAK inhibition promotes olfactory neuroplasticity following injury by increasing CNTF expression. Aim 1 will define the FAK-CNTF-CNTFRα pathway underlying GBC proliferation by first determining whether FAK inhibition induces CNTF in HBCs, OECs or both. We will also determine whether CNTF is released to activate CNTFRα signaling in stimulating GBC proliferation, and whether FAK inhibition acts through this intercellular mechanism. To increase the relevance of our findings, Aim 2 will determine whether FAK inhibition can increase olfactory neurogenesis via CNTF following acute OE injury. Thus, we will use acute injury with methimazole and determine whether injury increases CNTF in HBCs and/or OECs which leads to increased GBC proliferation and neurogenesis. The effect of FAK inhibitor treatment following methimazole may be within HBCs and/or OECs, something we will test. To prepare for additional studies, we will define an optimal dose of FAK inhibitor and then test whether CNTF mediates the effect of FAK inhibitor to promote OE neurogenesis after acute injury. Chronic olfactory inflammation inhibits HBC proliferation and increases FAK signaling in HBCs, suggesting that CNTF might be suppressed. To broaden the relevance to more types of olfactory injuries, Aim 3 will use a refined chronic olfactory inflammation mouse model to determine whether FAK inhibition increases CNTF and promotes GBC proliferation and olfactory neurogenesis. Aim 4 will determine the ability of FAK inhibition to promote OSN axonal growth and olfactory function recovery following acute and chronic types of OE injury, using genetic axon tracing methods combined with behavioral tests. This proposal will define the role of FAK and CNTF and validate the therapeutic potential of FAK inhibitors to improve olfactory function after injury. FAK inhibitors are well-tolerated in cancer clinical trials and intranasal administration avoids systemic side effects.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $370,643 )
2025	2025	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Research Related to Deafness and Communication Disorders	000	4	6/25/2025	NON-COMPETING CONTINUATION	$370,643
														Subtotal = $370,643

Issue Date FY: 2024 ( Subtotal = $371,039 )
2024	2024	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Research Related to Deafness and Communication Disorders	000	3	5/22/2024	NON-COMPETING CONTINUATION	$371,039
														Subtotal = $371,039

Issue Date FY: 2023 ( Subtotal = $371,399 )
2023	2023	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Research Related to Deafness and Communication Disorders	000	2	5/16/2023	NON-COMPETING CONTINUATION	$371,399
														Subtotal = $371,399

Issue Date FY: 2022 ( Subtotal = $371,727 )
2022	2022	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Research Related to Deafness and Communication Disorders	000	1	6/27/2022	NEW	$371,727
														Subtotal = $371,727

Grand Total All Awards = $1,484,808

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Improving olfactory neuroplasticity through FAK/CNTF signaling

Award Number: R01DC020528

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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