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Role of HCV exosomes in intercellular communication

Award Number: R01DK122737
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: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Role of HCV exosomes in intercellular communication - Program Director/Principal Investigator (Hahn, Young S.): Project Summary: Chronic HCV infection affects an estimated 3% of the world's population (>180 million people) and is a worldwide health problem causing end-stage liver diseases including hepatocellular carcinoma (HCC). The development of HCV-related HCC occurs by advanced fibrosis or cirrhosis. The clinical outcome of HCV infection and HCC risk depends on a balance between pro- and anti-inflammatory cytokines and the severity of liver inflammation. Our preliminary data show that exosomes released from HCV-infected hepatocytes contain the immunoregulatory molecules such as TGF-β. Importantly, HCV exosmes derived from infected hepatocytes promote intercellular communication with non-parenchymal cells such as Mφ and LSEC. As a result of receiving signaling from HCV exosomes, Mφ and LSEC are differentiated into fibrotic cells, that activate stellate cells and induce the development of liver fibrosis. The overall goal of this project is to define the mechanism by which HCV-derived exosomes from infected hepatocytes drive pro-fibrotic liver microenvironment and explore potential therapeutic agents to prevent liver fibrosis. In Aim 1, we propose to identify key molecular machinery required for the secretion of hepatocyte exosomes after HCV infection in in vitro and in vivo. In Aim 2, we will determine how HCV-derived exosomes induce the activation of fibrotic M2-like Mφ. In Aim 3, we will determine how HCV-derived exosomes induce fibrotic LSEC differentiation and explore a therapeutic strategy for preventing fibrosis. The studies proposed here will break new ground for identifying factors crucial for driving pro-fibrotic liver microenvironment and will help to develop novel therapeutic targets for the prevention of liver fibrosis. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


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 = $484,134 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	5	5/21/2024	SUPPLEMENT FOR EXPANSION	$7,698
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	5	5/20/2024	NON-COMPETING CONTINUATION	$25,445
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	2/28/2024	SUPPLEMENT FOR EXPANSION	$69,287
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	2/26/2024	NON-COMPETING CONTINUATION	$381,704
2024	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/19/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $484,134

Issue Date FY: 2023 ( Subtotal = $481,858 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	5/18/2023	SUPPLEMENT FOR EXPANSION	$57,743
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/1/2023	NON-COMPETING CONTINUATION	$424,115
														Subtotal = $481,858

Issue Date FY: 2022 ( Subtotal = $488,538 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/30/2022	NON-COMPETING CONTINUATION	$48,855
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/11/2022	NON-COMPETING CONTINUATION	$439,683
														Subtotal = $488,538

Issue Date FY: 2021 ( Subtotal = $422,710 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/26/2021	NON-COMPETING CONTINUATION	$422,710
														Subtotal = $422,710

Issue Date FY: 2020 ( Subtotal = $422,710 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/6/2020	NEW	$422,710
														Subtotal = $422,710

Grand Total All Awards = $2,299,950

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Role of HCV exosomes in intercellular communication

Award Number: R01DK122737

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: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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