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Hepatic stellate cells in liver homeostasis and regeneration

Award Number: R01DK133512
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: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Hepatic stellate cells in liver homeostasis and regeneration - The long-term goal of our research is to identify pro-regenerative to improve liver regeneration. The only curative therapy for end-stage liver disease is liver transplantation as no regenerative therapies exist. Liver transplantation is limited by donor graft supply. Living donor transplantation or split liver transplantation, in which one organ is split among two patients, rely on the regenerative capacity of the liver to restore its mass. The number of these interventions has increased to gap the bridge between demand and supply but post- hepatectomy or ‘small-for-size’ syndrome, which reflect a regenerative failure, present severe complications for which only supportive but no regenerative therapies exist. We have identified a novel hepatic growth factor, neurotrophin-3 (NTF3), that induces hepatocyte proliferation in culture and increases liver mass after administration to rodents. NTF3 is a member of the nerve growth factor family, that is secreted by hepatic stellate cells (HSC) and signals through tropomyosin kinase receptors (TRKs). While HSCs contribute to liver fibrogenesis during injury, HSCs are known to release growth factors which may be critical during liver regeneration. Using a novel HSC-depletion mouse model that used genetically engineered T cells to deplete HSCs after adoptive transfer, we discovered that HSCs maintain liver zonation, hepatocyte proliferation and liver mass. As liver regeneration occurs staggered in a zonal fashion to ensure functioning hepatocytes at any time during the process, liver zonation is critically important for liver regeneration. Our preliminary data indicate that HSCs and NTF3 promote liver regeneration and that NTF3-TRK signaling is relevant to humans as well. As there are known TRK-agonists and FDA-approved TRK-antagonists, our central hypothesis is that HSCs and HSC- derived NTF3 promote liver regeneration and that TRK-agonists improve liver regeneration. We will test our hypothesis in three specific aims: 1. To determine if NTF3 and TRK signaling maintain liver zonation and promote liver regeneration in rodent models of liver regeneration; 2. To establish NTF3 and TRK signaling in human liver, primary hepatocytes and hepatic organoids; 3. To clarify NTF3-TRK downstream signaling pathways in cultured liver cells. Our proposed studies will provide important insights into a novel hepatocyte growth signaling pathway and generate preclinical data to assess TRK-agonists for potential regenerative therapies.


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 = $680,622 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/18/2025	NON-COMPETING CONTINUATION	$68,063
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/18/2024	NON-COMPETING CONTINUATION	$612,559
														Subtotal = $680,622

Issue Date FY: 2024 ( Subtotal = $608,691 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/8/2023	NEW	$608,691
														Subtotal = $608,691

Grand Total All Awards = $1,289,313

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Hepatic stellate cells in liver homeostasis and regeneration

Award Number: R01DK133512

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: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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