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How Vitamin D Receptor Influences Intestinal Barriers

Award Number: R01DK114126
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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How Vitamin D Receptor Influences Intestinal Barriers - Salmonella enterica serotypes are invasive enteric pathogens spread through fecal contamination of food and water sources. It represents a constant public health threat in the U.S. and around the world. Impaired intestinal barriers are associated with bacterial infection. Vitamin D and its receptor (VDR) levels are inversely related to chronic inflammation in infectious diseases. The objective of this application is to study VDR regulation of intestinal tight junctions (TJs) in response to Salmonella infection. Our publications and preliminary data have shown that: (1) lack of VDR makes the host susceptible to Salmonella invasion; (2) Salmonella targets TJ proteins (e.g., ZO-1, Claudin) and facilitates pathogenic enteric bacterial invasion. (3) We have identified the sequence of functional vitamin D response element in Claudin- 5 and 15, two novel target genes of VDR; (4) impaired VDR leads to reduced expression of TJ proteins Claudin- 5 and 15, increased “leaky” protein Claudin 2, and increased permeability in infection; and (5) probiotics and their products enhance VDR function and inhibit Salmonella infection. Thus, we hypothesize that: “intestinal epithelial VDR regulation of barrier function is aberrant or lost in infectious states and restoring VDR function will attenuate severe infection and chronic inflammation.” We have now developed state-of-the-art transgenic models and cutting-edge methods, e.g., integrated three-dimensional microscopy for a spatial junction protein atlas and single-cell spatial proteomics for geographic profiling of the TJ protein expressions. Our research team includes experts in the following areas: epithelial biology, animal models, bioengineering, and microbiology. Two Specific Aims have been designed: Aim 1. Determine the cellular and molecular mechanisms by which intestinal VDR regulates barrier function that is essential for mucosal homeostasis. We will: A. Elucidate the mechanism for abnormal epithelial TJs coregulated by Claudins and their interactions in the VDR-/- organoids in vitro. B. Study regional and spatial Claudins, their interactions, and integrations with other barrier layers: microbiome and mucin. And C. Determine the mechanism for abnormal epithelial TJs, including spatial and omics studies of TJs, in the intestine of the VDRΔIEC and VDR overexpressed mice with or without infection. Aim 2. Investigate microbial metabolites and TJs vs. VDR for therapeutic strategies in inflammation and infection. We will A. Evaluate the roles and mechanisms of enhanced intestinal TJs vs. VDR expression by probiotic lactic acid bacterial proteins and metabolites in infected mice. B. Engineer probiotic bacteria strains for better outcomes in treatment of inflammation and infection. Our studies are innovative because they are focused on 1) understanding novel regulatory roles of VDR in Claudins and their interactions in infection; 2) developing cutting edge technologies and tools (organoids, transgenic mice, and spatial imaging) for studying intestinal biology; and 3) enhancing intestinal VDR expression by probiotics and microbial metabolites. This knowledge can then be exploited for strategies to prevent and treat digestive diseases by restoring VDR and enhancing barrier functions.


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 = $490,729 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	2/25/2026	NON-COMPETING CONTINUATION	$490,729
														Subtotal = $490,729

Issue Date FY: 2025 ( Subtotal = $496,297 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/15/2025	NON-COMPETING CONTINUATION	$496,297
														Subtotal = $496,297

Issue Date FY: 2024 ( Subtotal = $501,689 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/29/2024	COMPETING CONTINUATION	$501,689
2024	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $501,689

Issue Date FY: 2021 ( Subtotal = $359,775 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/3/2021	NON-COMPETING CONTINUATION	$359,775
														Subtotal = $359,775

Issue Date FY: 2020 ( Subtotal = $413,719 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/13/2020	NON-COMPETING CONTINUATION	$413,719
														Subtotal = $413,719

Issue Date FY: 2019 ( Subtotal = $413,719 )
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/29/2019	SUPPLEMENT FOR EXPANSION	$53,944
2019	2019	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/14/2019	NON-COMPETING CONTINUATION	$359,775
														Subtotal = $413,719

Issue Date FY: 2018 ( Subtotal = $358,697 )
2018	2018	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/20/2018	NEW	$358,697
														Subtotal = $358,697

Grand Total All Awards = $3,034,625

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How Vitamin D Receptor Influences Intestinal Barriers

Award Number: R01DK114126

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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