Thursday, December 26, 2024 12/26/2024

Interaction of the Microtubule Cytoskeleton and Perilipin-2 Regulates Hepatic Lipid Droplets - a Potential Therapeutic Target for Fatty Liver Disease

Award Number: K08DK123381
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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PROJECT SUMMARY/ABSTRACT The overall objective of this research is to target hepatocyte lipid droplets (LDs) for the development of therapeutic interventions for fatty liver disease. Hepatic steatosis, fat accumulation within hepatocyte LDs, is a key precursor for steatohepatitis which can lead to cirrhosis and hepatocellular cancer, necessitating liver transplantation. Unfortunately, hepatic steatosis also limits the number of donor livers acceptable for transplant as donor livers with severe steatosis have a high risk of primary nonfunction. As such, therapeutic strategies to reverse fatty liver are important for patients at risk for steatohepatitis and cirrhosis as well as to increase the donor pool of viable livers for transplantation. Our work focused on hepatocyte LDs herein shows three key observations: a) perilipin-2 (PLIN2), a LD-associated protein which regulates fat storage and utilization, co- localizes with and co-immunoprecipitates microtubules; b) microtubule disruption with nocodazole, a blunt microtubule targeting agent (MTA), uncouples PLIN2 from the LD, promotes LD fusion and yields delipidation (i.e. exocytotic secretion of LD contents) of steatotic hepatocytes with minimal cytotoxicity; and c) nocodazole promotes fat loss from ex vivo liver tissue with no effect on tissue viability. Based on these preliminary data, we propose the CENTRAL HYPOTHESIS that hepatocyte LDs are regulated by an interaction between PLIN2 and the microtubule cytoskeleton, and that this interaction is a potential therapeutic target to decrease the lipid burden of hepatocytes in fatty liver disease. Our SPECIFIC AIMS will test three hypotheses. FIRST, we will test the hypothesis that microtubules directly interact with LD-associated PLIN2. SECOND, we will test the hypothesis that microtubule perturbation increases lipolysis and leads to delipidation of steatotic hepatocytes. FINALLY, we will test the hypothesis that treatment of ex vivo steatotic liver tissue and ex vivo perfusion of steatotic livers with MTAs will lead to delipidation of hepatocytes and improved liver function in a pre-clinical model of organ salvage and rehabilitation. This work will provide foundational information to the emerging field of LD biology and is projected to demonstrate a novel cellular mechanism controlling hepatocyte LD dynamics and to identify therapeutic strategies to defat steatotic livers. The candidate is a basic scientist and transplant hepatologist, dedicated to improving the lives of patients with liver disease using a basic science approach. She is an Assistant Professor of Medicine at Mayo Clinic with a mentorship team consisting of Drs. Vijay Shah and Greg Gores. She has protected time for research and training activities, dedicated institutional funding for equipment and supplies, and a robust career development plan with specific activities and benchmarks that will position her for an independent research career. The comprehensive training plan will allow for the candidate to complete her current research plan and seek independent investigator status where she will translate these and future studies to human trials and future therapeutic interventions for patients.


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 = -$164,322 )
2025	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/26/2024	NON-COMPETING CONTINUATION	-$164,322
														Subtotal = -$164,322

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $165,780 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/23/2023	NON-COMPETING CONTINUATION	$165,780
														Subtotal = $165,780

Issue Date FY: 2022 ( Subtotal = $165,780 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/23/2022	NON-COMPETING CONTINUATION	$165,780
														Subtotal = $165,780

Issue Date FY: 2021 ( Subtotal = $165,780 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/19/2021	NEW	$165,780
														Subtotal = $165,780

Grand Total All Awards = $333,018

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Interaction of the Microtubule Cytoskeleton and Perilipin-2 Regulates Hepatic Lipid Droplets - a Potential Therapeutic Target for Fatty Liver Disease

Award Number: K08DK123381

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

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