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Pathobiology of Nonalcoholic Steatohepatitis

Award Number: R01DK130884
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: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Pathobiology of Nonalcoholic Steatohepatitis - PROJECT SUMMARY/ABSTRACT The long-term objective of this application is to define the molecular and cellular mechanisms that drive the pathogenesis of nonalcoholic steatohepatitis (NASH), with the goal of identifying therapeutic strategies. NASH is a progressive form of nonalcoholic fatty liver disease characterized by sublethal hepatocyte lipotoxicity (i.e., toxic lipid-induced cellular stress, which does not induce cell death) and consequent liver tissue inflammation. The overall objective of this proposal is to examine: (a) how sublethal lipotoxicity in hepatocytes triggers the release of extracellular vesicles (EVs) to augment liver immune infiltration by pathogenic CD4+ T helper cells; and (b) how these abnormal processes during NASH can be therapeutically reversed. To this end, we have made several pivotal observations. First, we found that sublethal lipotoxicity in hepatocytes activates Rho- associated protein kinase (ROCK) 1 by a caspase-6-dependent mechanism. Moreover, genetic ablation of ROCK1 specifically in hepatocytes attenuates NASH-associated liver injury and fibrosis in mice. Mechanistically, ROCK1 is critical for the release of lipotoxicity-induced EVs and their enrichment in activated leukocyte cell adhesion molecule (ALCAM), a ligand for the CD6 receptor expressed by CD4+ T cells. Consistent with ALCAM enrichment, hepatocyte-derived lipotoxic EVs significantly enhance migration of CD4+ T helper cells in an ALCAM-dependent manner. Finally, activated CD4+ T cells are enriched in NASH livers, and their depletion attenuates murine NASH. Based on these preliminary observations, we propose the CENTRAL HYPOTHESIS that sublethal lipotoxic signals induce ROCK1 activation in hepatocytes, which results in the release of pathogenic EVs that promote CD4+ T cell-mediated hepatic inflammation during NASH. We will now employ in vitro experimental approaches, animal models, and human biospecimens to examine the HYPOTHESIS in three integrated SPECIFIC AIMS. First, we will test the hypothesis that sublethal lipotoxicity activates ROCK1 through: a) an incomplete mitochondrial outer membrane permeabilization; and b) non-lethal proteolytic activity of caspase-6. Second, we will investigate how sublethal lipotoxicity in hepatocytes results in: a) the release of ALCAM-bearing EVs; and b) the stimulation of CD6 receptor expressed on CD4+ T helper cells, leading to their recruitment into the liver. Third, we will test the hypothesis that in a murine model of NASH: a) CD6 inhibition attenuates NASH by preventing CD4+ T cell infiltration of the liver; and b) specific ROCK1 inhibition reverses NASH progression. Finally, the human disease relevance of our findings from the preclinical studies will be assessed using well-annotated human liver tissue specimens. This technically and conceptually innovative application is also significant because it provides mechanistic insights into hepatocyte-to-CD4+ T helper cell crosstalk in NASH, thus identifying viable therapeutic interventions, such as inhibition of ROCK1 kinase activity or CD4+ T cell-associated CD6 receptor.


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 = $349,800 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/4/2025	NON-COMPETING CONTINUATION	$349,800
														Subtotal = $349,800

Issue Date FY: 2024 ( Subtotal = $335,808 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/9/2024	NON-COMPETING CONTINUATION	$335,808
														Subtotal = $335,808

Issue Date FY: 2023 ( Subtotal = $349,800 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/12/2023	NON-COMPETING CONTINUATION	$349,800
														Subtotal = $349,800

Issue Date FY: 2022 ( Subtotal = $349,800 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/17/2022	NON-COMPETING CONTINUATION	$349,800
														Subtotal = $349,800

Issue Date FY: 2021 ( Subtotal = $349,800 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/22/2021	NEW	$349,800
														Subtotal = $349,800

Grand Total All Awards = $1,735,008

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Pathobiology of Nonalcoholic Steatohepatitis

Award Number: R01DK130884

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: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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