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Specific-sized hyaluronan: a dual targeted therapy for ALD

Award Number: R01AA026764
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: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Specific-sized hyaluronan: a dual targeted therapy for ALD - ABSTRACT Alcoholic liver disease (ALD) develops in approximately 20% of alcoholics. The development of ALD is a complex process involving both parenchymal and non-parenchymal cells in the liver, as well as recruitment of immune cells in response to damage and inflammation. Innate immunity and inter-organ cross talk contribute to ethanol- induced liver injury with interactions between intestine and liver of particular importance. Impaired intestinal barrier function is associated with ethanol-induced liver injury in both humans and rodent models. Increased exposure of Kupffer cells, the resident hepatic macrophages, to gut-derived LPS during chronic ethanol activates TLR4-dependent production of inflammatory mediators. Chronic ethanol exposure also sensitizes Kupffer cells to LPS, resulting in increased production of inflammatory mediators. Hyaluronan (HA), an abundant extracellular matrix component, communicates with cells in a size-specific manner. Specific-sized HA fragments are either pro-inflammatory or anti-inflammatory, depending on the HA receptor and cell type involved in the response. We have discovered that specific-sized HA35 (average MW~35kD) normalizes TLR4- mediated signaling in Kupffer cells after chronic ethanol exposure and also protects mice from ethanol- induced gut and liver injury. By Next Generation Sequencing, we have identified a subset of microRNAs that are reciprocally regulated by HA35, providing novel insights into the mechanism of action for both ethanol and HA35 in regulating TLR4 signaling and macrophage polarization Furthermore, our team finds that specific-sized HA35 promotes intestinal health, at least in part by increasing expression of β-defensins and promoting the formation of tight junctions. Based on the multi-potent functions of HA35, here we will test the hypothesis that HA35 is a dually targeted therapeutic agent in ALD, normalizing Kupffer cell signal transduction after chronic ethanol exposure and protecting the intestinal epithelial barrier. We will address this hypothesis in three Specific Aims. Specific Aim 1: Investigate the mechanism for normalization of TLR4 signaling by HA35 in rat Kupffer cells and human PBMCs. Making use of both bioinformatics and cell based assays, we will 1) investigate the miRNA regulatory pathways reciprocally targeted by ethanol and HA35, which in turn regulate a) the control of nuclear-cytoplasmic shuttling and b) macrophage polarization. Specific Aim 2: Interrogate the impact of HA35 on maintenance of intestinal barrier function. We will use both cultured Caco-2 cells and mouse intestinal organoids to determine mechanisms for the direct effect of HA35 on protecting tight junctions from ethanol. Specific Aim 3: Test the ability of HA35 to prevent and treat chronic ethanol-induced intestinal and liver injury in mice. Importantly, medical grade HA for device-use is commercially available, thus enhancing the likelihood for a rapid translation of our studies on the dually protective functions of HA35 in chronic ethanol exposure into clinical investigations in ALD.


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 = $0 )
2026	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	5	12/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	5	3/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $468,842 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	5	8/1/2022	NON-COMPETING CONTINUATION	$468,842
														Subtotal = $468,842

Issue Date FY: 2021 ( Subtotal = $411,861 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	4	7/27/2021	NON-COMPETING CONTINUATION	$411,861
														Subtotal = $411,861

Issue Date FY: 2020 ( Subtotal = $411,861 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	3	7/31/2020	NON-COMPETING CONTINUATION	$411,861
														Subtotal = $411,861

Issue Date FY: 2019 ( Subtotal = $409,302 )
2019	2019	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	2	7/12/2019	NON-COMPETING CONTINUATION	$409,302
														Subtotal = $409,302

Issue Date FY: 2018 ( Subtotal = $409,302 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Alcohol Research Programs	000	1	7/31/2018	NEW	$409,302
														Subtotal = $409,302

Grand Total All Awards = $2,111,168

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Specific-sized hyaluronan: a dual targeted therapy for ALD

Award Number: R01AA026764

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: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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