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The Role of FXR on the Intestinal Barrier in Acute Injury.

Award Number: K08DK123377
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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The Role of FXR on the Intestinal Barrier in Acute Injury. - Project Summary/Abstract The goal of this proposal is to advance as a surgeon-scientist to become an independent investigator through completion of the proposed research project and career development under the oversight of an outstanding mentoring team of gastrointestinal and FXR signaling experts. The career development described will provide foundational insight as I design experimental approaches and assess study outcomes. This award will also support the protected time needed to establish a strong publication record in the field of intestinal physiology and develop preliminary data for a competitive R level submission. The farnesoid X receptor (FXR) is a key bile acid receptor that influences the intestinal epithelial barrier. While activation of FXR seems to be beneficial in chronic injury models of the intestine, our preliminary data show that in acute, inflammatory injury, FXR activation is deleterious. FXR knock-out (KO) animals, in contrast, are protected from acute injury. In this proposal, we will define the role of FXR in intestinal barrier function during acute injury. We hypothesize that FXR activation compromises intestinal barrier function by upregulating small heterodimer protein (SHP), while interfering with EGFR signaling, leading to tight junction disruption. We will test this hypothesis with the following specific aims: 1) Determine the mechanisms involved in FXR regulating intestinal epithelial barrier function, and 2) Test the effect of tissue-specific FXR inhibition on the intestinal bar- rier using acute injury models in vivo. We will determine the role of FXR and its downstream effector SHP in intestinal barrier function in vitro and in vivo. To explore this, we will use enteroid-derived monolayers from wild type, FXR KO, SHO KO, and EGFR dominant-negative ‘Velvet’ mice to determine the effects on the intestinal barrier and tight junctional proteins with and without injury. We will determine FXR and EGFR signal activation using qPCR and Western blot anal- yses. We will determine the role of macrophages using bone marrow-derived culture from genetically-modified animals. These in vitro findings will be tested in vivo using an LPS-injection model of acute injury, utilizing FXR (whole body, intestinal-specific, and macrophage-specific) and SHP KO mice. Cecal ligation and puncture will be used to test pharmacologic manipulation of the FXR pathway on disease progression. This project will begin to establish the role of FXR regulation of the intestinal epithelial barrier in the setting of acute injury. Long term, these findings will provide needed insight into the development of preventative and therapeutic strategies in gut origin sepsis, inflammatory bowel disease, or other GI pathologies. This research has the potential to improve the outcomes of patients with diseases that affect intestinal integrity through better understanding of the mechanisms of FXR-mediated intestinal barrier function.


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 = $0 )
2025	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $170,856 )
2024	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/7/2023	NON-COMPETING CONTINUATION	$170,856
														Subtotal = $170,856

Issue Date FY: 2023 ( Subtotal = $170,856 )
2023	2023	CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/13/2022	NON-COMPETING CONTINUATION	$170,856
														Subtotal = $170,856

Issue Date FY: 2022 ( Subtotal = $170,856 )
2022	2022	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/6/2022	NON-COMPETING CONTINUATION	$170,856
														Subtotal = $170,856

Issue Date FY: 2021 ( Subtotal = $170,856 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/15/2020	NON-COMPETING CONTINUATION	$170,856
														Subtotal = $170,856

Issue Date FY: 2020 ( Subtotal = $172,356 )
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/27/2020	NEW	$172,356
														Subtotal = $172,356

Grand Total All Awards = $855,780

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The Role of FXR on the Intestinal Barrier in Acute Injury.

Award Number: K08DK123377

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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