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Studies of a new checkpoint regulator in the control of intestinal inflammation

Award Number: R01AI155488
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/07/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Studies of a new checkpoint regulator in the control of intestinal inflammation - Project Summary The innate immune system is the first line of host defense against invading pathogenic microorganisms. Innate immune cells can recognize these pathogens to induce cytokines against infections. However, this immune response must be tightly regulated to effectively eliminate invading microorganisms while minimizing tissue inflammation. Protein ubiquitination is important both in signal transduction and in proteasome-mediated protein degradation and is a pivotal regulatory mechanism for the innate immune system. A key component of the ubiquitination system is E3 ligase to specifically recognize the substrate for modification. We recently found that a TRIM family member, E3 ligase TRIM29, is highly expressed in intestinal epithelial cells (IECs). IECs act as a physical barrier between the external environment and the mucosal immune system. Importantly, after activation, IECs become innate immune-like cells to produce robust proinflammatory cytokines. We posit that TRIM29 is a key immune regulator to suppress innate immune response in a cell/tissue-specific manner to reduce intestinal inflammation. Notably, in the gut, genes encoding inflammasome components such as CARD9, NLRP3 and Caspases are associated with intestinal inflammation, and mice deficient in these genes are susceptible to colitis and fungal infection. However, hyperactive inflammasome signaling and uncontrolled IL-1 family cytokines lead to immune disorders and inflammatory disease. For instance, overproduction of inflammasome cytokine IL-18, excessive activation of NLRP3-inflammasome, or aberrant immune response to fungus play a major pathogenic role in colitis. Thus, this immune response must be finely tuned during immune activation for optimal protection against infections while avoiding unwanted inflammation. However, little is known about how such activation is terminated. Our preliminary studies show that TRIM29 negatively regulates IL-1 family cytokines produced by IECs during colitis or fungal infection. Moreover, expression of TRIM29 itself is significantly downregulated in inflamed colons, whereas production of IL-1 family cytokines is elevated. However, it is unknown whether lost expression of TRIM29 is regulated by IL-1 family cytokines and/or epigenetic modifications to control responses to environment stimuli in the intestines. We hypothesize that TRIM29 expression in IECs is a checkpoint regulator of IL-1 family cytokines crucial to reduce intestinal inflammation in colitis and fungal infection. We propose the following three aims to test this hypothesis: (1) To dissect molecular pathways that control TRIM29 expression in epithelial cells under normal and inflammatory conditions; (2) To define the mechanism by which TRIM29 inhibits IL-1 inflammation; (3) To investigate in vivo functions of TRIM29 in regulating IECs function in colitis and anti-fungal immunity.


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: 2026 ( Subtotal = $0 )
2026	2025	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	3/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $403,750 )
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	5	7/21/2025	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2024 ( Subtotal = $403,750 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	4	5/28/2024	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2023 ( Subtotal = $403,750 )
2023	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	3	5/17/2023	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2022 ( Subtotal = $403,750 )
2022	2022	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	2	5/12/2022	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2021 ( Subtotal = $403,750 )
2021	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	1	7/2/2021	NEW	$0
2021	2021	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	6/7/2021	NEW	$403,750
														Subtotal = $403,750

Grand Total All Awards = $2,018,750

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Studies of a new checkpoint regulator in the control of intestinal inflammation

Award Number: R01AI155488

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/07/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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