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Role of epithelial cell intrinsic vitamin A metabolism in regulating immune function in the gut

Award Number: R01DK113265
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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PROJECT SUMMARY Vitamin A or retinol is amongst the most well characterized food-derived nutrients with diverse immune- modulatory roles. Deficiency in dietary vitamin A has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders. To maintain sufficient levels of vitamin A, the body relies on the uptake of retinol from the intestinal lumen by intestinal epithelial cells or IECs. After uptake by IECs, retinol can either be processed for storage or be further metabolized into retinoic acid (RA). Even though IECs are at the center of Vitamin A metabolism and play a dominant role in controlling the fate of dietary vitamin A, our knowledge of how IEC intrinsic vitamin A metabolic machinery is regulated is extremely superficial. By comparing germ-free (GF) and conventional (CV) mice we demonstrate that gut bacteria play a critical role in modulating retinoic acid (RA) levels and expression of vitamin A metabolic machinery in the intestinal epithelium. Specifically, we find bacteria differentially regulate expression of retinol dehydrogenase 7 (rdh7), a key gene involved in conversion of retinol into RA in the intestinal epithelium. By employing genetic mouse models harboring a deletion in rdh7 in IECs, we establish that IEC intrinsic RA production regulates the levels of Interleukin IL-22, a key cytokine that controls barrier responses to gut bacteria. Our data demonstrates for the first time that gut bacteria-dependent RA synthesis is critical for regulating local immune responses. Current proposal seeks to understand the molecular mechanism by which gut bacteria regulate RA synthesis and vitamin A metabolic gene rdh7 in IECs (Aim1), establish the role of rdh7 expression in IECs in regulating RA-signaling in the gut (Aim 2) and determine the role of IEC-intrinsic vitamin A metabolism on host-microbe homeostasis via modulation of IL-22 levels in the gut (Aim 3). To accomplish these goals, we have developed innovative genetic approaches that enable us to conditionally delete or over-express rdh7 specifically in IECs. Further we propose to utilize novel methodologies such as monoassociated and gnotobiotic mouse models to delineate the bacterial cues that regulate RA generation in the intestinal epithelium. Our experimental methodology incorporates robust analytical approaches such as tandem mass-spectrometry (LC-MS/MS) that enables us to accurately determine the flux in vitamin A metabolic pathway in response to discrete bacterial cues. This work will be significant because it will establish mechanistic links between gut bacteria and intestinal epithelium intrinsic vitamin A metabolic pathway. Moreover, it will test the feasibility of manipulating mucosal immunity by bacterial modulation of IEC intrinsic vitamin A metabolism for therapeutic purposes.


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: 2022 ( Subtotal = $448,470 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/30/2022	NON-COMPETING CONTINUATION	$44,849
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/1/2022	NON-COMPETING CONTINUATION	$403,621
														Subtotal = $448,470

Issue Date FY: 2021 ( Subtotal = $448,470 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/25/2021	NON-COMPETING CONTINUATION	$448,470
														Subtotal = $448,470

Issue Date FY: 2020 ( Subtotal = $448,470 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/16/2020	NON-COMPETING CONTINUATION	$448,470
														Subtotal = $448,470

Issue Date FY: 2019 ( Subtotal = $448,470 )
2019	2019	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/12/2019	NON-COMPETING CONTINUATION	$448,470
														Subtotal = $448,470

Issue Date FY: 2018 ( Subtotal = $462,531 )
2018	2018	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/14/2018	NEW	$462,531
														Subtotal = $462,531

Grand Total All Awards = $2,256,411

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Role of epithelial cell intrinsic vitamin A metabolism in regulating immune function in the gut

Award Number: R01DK113265

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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