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Role of Exosomal microRNAs in Alcohol-induced Liver Injury

Award Number: R21AA025429
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2021

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Role of Exosomal microRNAs in Alcohol-induced Liver Injury - Abstract Globally alcoholic liver disease (ALD) remains a leading cause of morbidity and mortality. ALD results from chronic inflammation and oxidative stress and hepatocyte death which releases a variety of cellular injury and damage associated molecules, apoptotic bodies, microvesicles (MV) and exosomes (EXOs) into the hepatic microenvironment activating other hepatic cell types. This chronic injury results in an exacerbated wound-healing response characterized by excess collagen deposition that can lead to fibrosis/cirrhosis and hepatocellular carcinoma. Alcohol is hepatotoxic, but its metabolism drives oxidative stresses contributing to hepatic pathology. Multiple cell types in the liver are required to coordinate a response to this chronic injury. Hepatic stellate cells (HSCs) transdifferentiate from a quiescent to an activated myofibroblast-type cell that is the primary effector of collagen deposition. Hepatic macrophages, Kupffer cells (KC) regulate innate inflammatory responses and hepatic remodeling. Coordination of repair and remodeling requires intracellular communication. The intimate arrangement of these cells in hepatic microenvironment facilitates the transfer of exosomes (EXOs) between the cell populations. EXOs are vesicles of 30-100 nm that are produced by all active or resting cells and are packaged with microRNA (miR), mRNA and protein cargo. EXOs can be found in tissues, blood and other bodily fluids where they can functionally transfer their contents to recipient cells inducing changes in gene expression and activity. EXO-mediated transfer of miRs may exert local control on HSC activation and KC function during alcohol-induced injury. miRs, small non-coding RNAs, are critical regulators of gene expression that influence all cellular physiological functions, and they are a major component of EXO cargo. We have identified that EXO secretion is increased in activated HSCs, and that the miR profiles change on activation. In addition, EXOs from activated HSCs interact with macrophages to suppress the inflammatory immune response in cells exposed to bacterial endotoxin. Based on these data we hypothesize that EXOs secreted by HSCs during alcohol-induced liver injury deliver unique miR cargo that can modulate KC responses and coordinate tissue repair during hepatic injury. In aim 1 we will identify changes in miRs profiles from HSC- EXOs in models of alcohol-induced injury. In aim 2 we will identify membrane and internal protein and RNA (mRNA, miR, etc.) cargo from HSC-EXOs that may facilitate cellular uptake and define miR:mRNA interactions that may direct and coordinate KC function. Much remains unknown about the cellular exchange and role of EXOs in ALD pathology. The approach in this application is innovative as it will identify exosomal miRs from activated HSCs that serve to locally modulate KC function. In addition, using models of alcohol-induced hepatic injury with a novel method of extracting tissue specific exosomes we will more directly determine their role in hepatic pathology. We anticipate these studies will reveal novel diagnostic/prognostic indicators and identify new therapeutic targets.


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: 2023 ( Subtotal = $0 )
2023	2019	THE CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY	1000 BLYTHE BLVD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	2	11/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$180 )
2022	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	2	3/8/2022	NON-COMPETING CONTINUATION	-$180
														Subtotal = -$180

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	2	7/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $184,063 )
2019	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	001	2	7/9/2019	NON-COMPETING CONTINUATION	$0
2019	2019	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	2	2/20/2019	NON-COMPETING CONTINUATION	$184,063
														Subtotal = $184,063

Issue Date FY: 2018 ( Subtotal = $222,813 )
2018	2018	CHARLOTTE-MECKLENBURG HOSPITAL AUTHORITY, THE	1000 BLYTHE BOULEVARD	CHARLOTTE	NC	28203	MECKLENBURG	USA	Alcohol Research Programs	000	1	3/14/2018	NEW	$222,813
														Subtotal = $222,813

Grand Total All Awards = $406,696

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Role of Exosomal microRNAs in Alcohol-induced Liver Injury

Award Number: R21AA025429

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2021

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