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CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis

Award Number: R01DK115406
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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The overarching theme of this project is to address the mechanisms underlying gut derived extracellular vesicles (EVs)-induced liver inflammation/injury in Non-alcoholic fatty liver disease (NAFLD). We will determine the role of sphingolipid metabolites, specifically; Sphingosine 1-phosphate (S1P)-enriched gut EVs and pathway CSN8/SphK1 in the development of NAFLD. The current proposal links gut-derived EVs to macrophage- mediated inflammation by proposing that extracellular vesicles from gut recruit macrophages to the liver, resulting in liver injury and inflammation. Our recent work has begun to identify intestinal inflammation-induced alterations in EVs, and shows that gut-derived EVs play a critical role in the regulation of NKT cells and Th17 cells in the development of liver inflammation and colon cancer via gut-liver axis. Our preliminary data shows that LPS promotes Intestinal epithelial cells (IECs) release sphingolipid metabolites-enriched pro-inflammatory EVs including ceramide and S1P. Our preliminary findings also indicate that CSN8/SphK1 signaling pathway plays a crucial role in the production of S1P-enriched EVs. Chronic high fat diet consumption leads to increased gut permeability and expose the liver to gut-derived products including EVs of IECs. Increased S1P-enriched EVs activate its receptor S1P1 on hepatic macrophages, which may promote macrophage chemotaxis into the liver. This has led to the central hypothesis that gut microbiota regulate sphingolipid metabolites- enriched EVs biogenesis and release via gut CSN8/SphK1 pathway and gut EVs carrying sphingolipid metabolites (ceramide and S1P) translocate to liver, which in turn attract macrophages into the liver promoting liver injury in NAFLD. Importantly, the proposal also pursues translational studies that examine the efficacy of nutrition-nanoparticles based therapeutic interventions targeted at gut microbiota and SphK1-S1PR1 inhibition in mitigating gut-liver axis changes. To address our hypothesis, we propose the following specific aims: Aim 1: Determine whether gut-derived EVs-S1P regulate liver inflammation and injury via CSN8/SphK1 pathway in NAFLD. Aim 2: Determine whether gut-derived EVs-S1P contribute to liver macrophages recruitment/activation by S1PR1-STAT3 in NAFLD. Aim 3: Define molecular mechanisms underlying CSN8 and SphK1 reciprocal regulation and modulation of the CSN8/S1P-S1PR1 signal will prevent macrophages mediated-liver injury in NAFLD. The proposal will provide a better understanding of diet-gut-liver interactions and molecular mechanisms contributing to the pathogenesis of EVs-S1P-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating NAFLD.


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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $390,621 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/4/2022	NON-COMPETING CONTINUATION	$390,621
														Subtotal = $390,621

Issue Date FY: 2021 ( Subtotal = $397,195 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/14/2021	NON-COMPETING CONTINUATION	$397,195
														Subtotal = $397,195

Issue Date FY: 2020 ( Subtotal = $403,582 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/15/2020	NON-COMPETING CONTINUATION	$403,582
														Subtotal = $403,582

Issue Date FY: 2019 ( Subtotal = $409,783 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/11/2019	NON-COMPETING CONTINUATION	$409,783
														Subtotal = $409,783

Issue Date FY: 2018 ( Subtotal = $415,800 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/16/2018	NEW	$415,800
														Subtotal = $415,800

Grand Total All Awards = $2,016,981

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CSN8 regulation of S1P-enriched extracellular vesicles to modulate NAFLD by gut-liver axis

Award Number: R01DK115406

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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