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Hepatic TrkB-T1 signaling in NASH pathogenesis and resolution

Award Number: R01DK136177
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: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Hepatic TrkB-T1 signaling in NASH pathogenesis and resolution - Project Summary/Abstract Nonalcoholic steatohepatitis (NASH) is a progressive metabolic liver disease characterized by persistent liver injury, inflammation, and fibrosis. Reprogramming of intrahepatic signaling and liver microenvironment is a hallmark of NASH pathogenesis in mice and humans. However, the molecular nature of pathophysiological signaling that drives NASH progression remains an important unsolved question. To address this critical knowledge gap, we performed bulk and single-cell transcriptomic analysis on healthy and diet-induced NASH mouse livers. Our work revealed several transcriptomic signatures of NASH, liver cell heterogeneity and reprogramming during disease pathogenesis, and the landscape of intercellular crosstalk in the liver. Importantly, key features of NASH-associated reprogramming of the liver microenvironment and intrahepatic signaling in mice are notably conserved in human NASH. Hepatocytes respond to metabolic stresses in NASH by engaging adaptive and maladaptive signaling pathways that ultimately lead to liver steatosis and hepatocyte injury. In preliminary studies, we observed that hepatic expression of the truncated isoform of Tropomyosin receptor kinase B (TrkB), TrkB-T1, but not the full-length TrkB isoform, was selectively and markedly upregulated in mouse and human NASH. However, whether and how aberrant activation of hepatic TrkB-T1 signaling contributes to NASH pathogenesis has not been explored. Based on a body of preliminary data, we hypothesize that pathogenic activation of TrkB-T1 signaling sensitizes hepatocytes to stress-induced injury. In this proposal, we plan to investigate the role of TrkB-T1 in liver injury and NASH progression. We will explore cell-intrinsic and extrinsic mechanisms that mediate the effects of TrkB-T1 on NASH pathogenesis. Finally, we will explore the therapeutic potential of targeting this pathway for NASH treatment. Successful completion of this project will provide novel insights into the pathophysiology of NASH and generate critical preclinical data that will guide future translational work.


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 = $603,537 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/6/2026	NON-COMPETING CONTINUATION	$603,537
														Subtotal = $603,537

Issue Date FY: 2025 ( Subtotal = $540,153 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/7/2025	NON-COMPETING CONTINUATION	$540,153
														Subtotal = $540,153

Issue Date FY: 2024 ( Subtotal = $576,164 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/15/2024	NON-COMPETING CONTINUATION	$36,011
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/27/2023	NON-COMPETING CONTINUATION	$540,153
														Subtotal = $576,164

Issue Date FY: 2023 ( Subtotal = $578,684 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/2/2023	NEW	$578,684
														Subtotal = $578,684

Grand Total All Awards = $2,298,538

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Hepatic TrkB-T1 signaling in NASH pathogenesis and resolution

Award Number: R01DK136177

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: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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