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Novel regulation of mucosal innate defense by AMPK in Otitis Media

Award Number: R01DC019512
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: 04/07/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Novel regulation of mucosal innate defense by AMPK in Otitis Media - Mucin, a major protein component in mucus, plays a critical role in mucosal innate defense by providing a physical barrier and trapping pathogens for mucociliary clearance. If uncontrolled, excessive mucin production overwhelms mucociliary clearance and causes conductive hearing loss in otitis media (OM) and mucus obstruction in lung infections. Therefore, mucin production must be tightly regulated. However, the molecular mechanisms underlying the tight regulation of mucin remain largely unknown. Otitis media (OM) is the most common childhood bacterial infection and the leading cause of conductive hearing loss. It remains a major health problem and a substantial socioeconomic burden. S. pneumoniae, Sp, represents a major gram-positive bacterial pathogen for OM. Currently available Sp vaccines have a limited impact on OM. Moreover, inappropriate antibiotic use increased antibiotic-resistance. There is an urgent need for developing innovative non-antibiotic therapeutic agent for suppressing mucus overproduction. Our long-term goal is to elucidate the molecular mechanisms underlying OM pathogenesis and identify novel therapeutic targets. In contrast to the relatively well-known toll-like receptor (TLR)-dependent mechanisms by which Sp and pneumolysin (PLY – a key virulence factor produced by virtually all clinical Sp isolates) induce host mucosal immune response, the TLR-independent mechanisms including the key regulators remain largely unclear. Adenosine 5’-monophosphate-activated protein kinase α1 (AMPKα1) has emerged as a master regulator of host energy homeostasis. Its role in infectious diseases, in particular in the host mucosal innate defense response, e.g. mucus production, remains largely unclear. Our encouraging preliminary data suggest that Sp and PLY may up-regulate mucin MUC5AC and MUC5B via activation of AMPKα1 in a TLR2/4-independent manner in the middle ear and airway epithelial cells in vitro and in the mouse models of both acute and chronic OM. Interestingly, Sp and PLY may activate AMPKα1 by inducing novel non-traditional (protein degradation- independent) ubiquitination of AMPKα1 likely via downregulating a key deubiquitinase CYLD. Together, these exciting preliminary data have thus provided a solid foundation for us to hypothesize that [1] AMPKα1 acts as a key regulator for Sp-induced up-regulation of MUC5AC and MUC5B via TLR-independent signaling; [2] Activation of AMPKα1 by interplay between polyubiquitination and phosphorylation plays a critical role in Sp- induced up-regulation of MUC5AC and MUC5B (hypothesis). To test our hypothesis, we will pursue two specific aims to determine (Aim 1) the role of AMPKα1 in OM pathogenesis in both AOM and COM; and (Aim 2) how Sp activates AMPKα1. These studies will significantly advance our understanding of the key regulators including AMPK in TLR-independent host mucosal innate defense in bacterial infections and lead to the identification of novel therapeutic targets for controlling mucus overproduction. Our AMPK signaling studies may also help understand molecular mechanisms of other AMPK-related diseases (Significance and Impact).


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 = $460,120 )
2025	2025	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Research Related to Deafness and Communication Disorders	001	5	4/23/2025	NON-COMPETING CONTINUATION	$46,011
2025	2025	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Research Related to Deafness and Communication Disorders	000	5	4/8/2025	NON-COMPETING CONTINUATION	$414,109
														Subtotal = $460,120

Issue Date FY: 2024 ( Subtotal = $460,120 )
2024	2024	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Research Related to Deafness and Communication Disorders	000	4	3/28/2024	NON-COMPETING CONTINUATION	$460,120
														Subtotal = $460,120

Issue Date FY: 2023 ( Subtotal = $460,120 )
2023	2023	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION INC	58 EDGEWOOD AVE NE	ATLANTA	GA	30303	FULTON	USA	Research Related to Deafness and Communication Disorders	000	3	3/30/2023	NON-COMPETING CONTINUATION	$460,120
														Subtotal = $460,120

Issue Date FY: 2022 ( Subtotal = $460,120 )
2022	2022	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Research Related to Deafness and Communication Disorders	000	2	4/1/2022	NON-COMPETING CONTINUATION	$460,120
														Subtotal = $460,120

Issue Date FY: 2021 ( Subtotal = $459,752 )
2021	2021	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.	58 EDGEWOOD AVE NE 3RD FL	ATLANTA	GA	30303	FULTON	USA	Research Related to Deafness and Communication Disorders	000	1	4/7/2021	NEW	$459,752
														Subtotal = $459,752

Grand Total All Awards = $2,300,232

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Novel regulation of mucosal innate defense by AMPK in Otitis Media

Award Number: R01DC019512

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: 04/07/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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