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STING signaling in T cells regulation of intestinal homeostasis and inflammatorybowel diseases

Award Number: R01DK124132
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT STING (stimulator of interferon genes), a cytoplasmic sensor for cyclic dinucleotides (CDNs), plays a crucial role as an adaptor molecule for a number of intracellular DNA receptors. The upstream DNA sensors that signal through STING include cyclic GMP-AMP synthase (cGAS), IFN-inducible proteins, and DExD/H-box helicase family proteins, highlighting an important function for STING in controlling multiple DNA recognition pathways. STING has been crucial in host defense against viral, bacterial, and eukaryotic pathogens, and also to the development of autoimmune disease. Abnormalities in this defense mechanism can underpin a spectrum of conditions, including cancer and autoinflammatory diseases. STING is thus a highly promising drug target. Recent studies have underscored the role of STING in regulating intestinal inflammation and tumorigenesis. As high levels of microbiota-derived DNA and CDNs are present in the gut, these stimuli could contribute to local activation of STING at steady state. Sting-/- mice have been reported to develop more severe colitis upon acute inflammatory insult. Our preliminary data demonstrated that T cells expressed STING at levels higher than that in dendritic cells (DCs). Furthermore, activation of STING signaling promoted T cell production of IL-10 and IL- 22 but inhibited IL-17 production, indicating that STING may potentially regulate intestinal homeostasis and colitis development by promoting anti-inflammatory IL-10/IL-22 and inhibiting proinflammatory cytokine production by T cells. In this application, we will test whether STING promotes T cell production of IL-10 and IL-22 by inducing IRF4 and AHR expression mediated by the production of type I IFNs by both T cells and dendritic cells, which would lead to the preservation of intestinal immune homeostasis and inhibition of IBD. Furthermore, we will test whether STING agonists can prevent and treat colitis.


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: 2023 ( Subtotal = $503,932 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/5/2023	NON-COMPETING CONTINUATION	$503,932
														Subtotal = $503,932

Issue Date FY: 2022 ( Subtotal = $503,932 )
2022	2022	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/14/2022	NON-COMPETING CONTINUATION	$503,932
														Subtotal = $503,932

Issue Date FY: 2021 ( Subtotal = $503,932 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/21/2021	NON-COMPETING CONTINUATION	$503,932
														Subtotal = $503,932

Issue Date FY: 2020 ( Subtotal = $503,932 )
2020	2020	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/17/2020	NEW	$503,932
														Subtotal = $503,932

Grand Total All Awards = $2,015,728

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STING signaling in T cells regulation of intestinal homeostasis and inflammatorybowel diseases

Award Number: R01DK124132

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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