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Essential functions of OGT in host defense mechanism

Award Number: R35GM152205
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Essential functions of OGT in host defense mechanism - Project Summary Cellular metabolism instructs immune cell functions in both physiological and disease conditions. Activation of immune cells in response to invading pathogens induces a robust metabolic reprogramming, which has been indicated to play a critical role in orchestrating immune cell functions. The possibility of modulating immune cell function through metabolic regulation represents a new strategy to strengthen host defense mechanism. However, the role of individual metabolic pathways and enzymes during pathogen infection is not well understood, which represents a critical knowledge gap. Recently, we have identified the O-GlcNAc transferase (OGT), an important glucose metabolism enzyme, as a critical regulator of innate immune signaling during virus infection and septic inflammation. OGT mediates a ubiquitous post-translational modification (PTM) of cytosolic and nuclear proteins, known as O-GlcNAcylation. OGT-mediated O-GlcNAc signaling is well known as an essential regulator of many fundamental aspects of cell physiology and dysregulated O-GlcNAc signaling occurs in numerous human diseases. Despite a broad pathophysiological significance of OGT, the function of OGT in host defense mechanism against pathogen infection is just emerging and still underappreciated. Our preliminary results indicate that OGT directly restricts intracellular replication of both virus and bacteria, in addition to its previously established impacts on regulating innate immune signaling. By studying cell and mouse models with either OGT gene-deletion (Ogt-KO) or enzyme-inactive OGT (OgtK908A), we observed both enzyme-dependent and -independent functions of OGT in modulating innate immune signaling and limiting intracellular pathogen replication. We hypothesize that OGT serves as a central component of host defense mechanism by sensing pathogen infection and integrating innate immune signaling and cellular lipid metabolism via both enzyme activity-dependent and -independent manner. The long-term objective of our work is to determine the principles, functions and mechanisms of OGT and O-GlcNAc signaling in health and diseases. In this proposal, we aim to use our newly developed OGT enzyme-inactive mouse model and OGT gene-deletion model to understand the molecular mechanism by which OGT mediates host defense responses against invading virus and bacteria. We will advance this goal through three directions: 1) how does OGT sense virus infection and integrate innate immune response and cellular fatty acid synthesis pathway? 2) what is the functional importance of OGT-mediated protein O- GlcNAcylation in the detection of intracellular bacteria? and 3) how does the ubiquitination of OGT affect host defense? This study will significantly advance the field of immunometabolism by elucidating the function and mechanism of an important metabolic enzyme sensing and antagonizing pathogen infection. Successful development of OGT enzyme-inactive mouse model will also benefit other research topics such as cancer, diabetes and neurodegenerative diseases.


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 = $387,489 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	001	2	6/17/2025	NON-COMPETING CONTINUATION	$387,489
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	11/6/2024	NEW	$0
														Subtotal = $387,489

Issue Date FY: 2024 ( Subtotal = $387,489 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Biomedical Research and Research Training	000	1	9/4/2024	NEW	$387,489
														Subtotal = $387,489

Grand Total All Awards = $774,978

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Essential functions of OGT in host defense mechanism

Award Number: R35GM152205

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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