Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Leveraging the nutrient sensing and degradative capacity of lysosomes in macrophages as a novel therapeutic approach in cardiovascular disease

Award Number: R35HL183548
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2033

Group Awards By:

View Award Description

Leveraging the nutrient sensing and degradative capacity of lysosomes in macrophages as a novel therapeutic approach in cardiovascular disease - Project Summary Atherosclerosis is the underlying cause of the majority of cardiovascular diseases including myocardial infarction, strokes, and heart failure leading to tremendous morbidity and mortality worldwide. Risk factor modification such as reductions in hyperlipidemia and hypertension constitute the primary treatments available for this vexing disease. Thus, there is an active effort to identify the culprit cellular processes that provide mechanistic insight. Various lines of evidence demonstrate a progressive dysfunction in the autophagy-lysosome system of plaque macrophages, leading to an inability to degrade excess lipids and cytotoxic materials accumulating in the atherosclerotic plaque. Thus, attempts at reprogramming the degradative capacity of macrophages might be a fruitful therapeutic area. Our work with TFEB, the predominant transcription factor regulating autophagy- lysosomal biogenesis, shows that enhancing this pathway in macrophages leads to reductions in atherosclerosis of mice. We have also uncovered a regulatory mechanism involving two key nutrients (amino acids and cholesterol), lysosomal nutrient-sensing, and mTORC1 which potently suppresses TFEB and the autophagy- lysosome system in macrophages. Furthermore, we have shown that dietary manipulation of dietary protein and lipids which affect circulating nutrients are key drivers of macrophage mTORC1 signaling. This raises the prospect that targeting nutrient-mediated mTORC1 activation and its regulation of the macrophage degradative response can be a novel therapeutic strategy in cardiovascular disease. In in R35 proposal, we leverage our decades-long experience, track-record, and active NHLBI funding in this area to propose a broad-ranging research program linking nutrition with lysosomal nutrient-sensing, mTOR, TFEB, and the autophagy-lysosome degradative response in macrophage. Our proposal focuses on three distinct but interrelated themes with theme 1 focused on understanding the downstream effects of TFEB in macrophages, theme 2 focused on the drivers of macrophage mTORC1 activation via lysosomal nutrient-sensing, and theme 3 focused on how dietary manipulation can affect macrophage nutrient-sensing and its degradative potential.


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 = $756,607 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	3/16/2026	NEW	$756,607
														Subtotal = $756,607

Grand Total All Awards = $756,607

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Leveraging the nutrient sensing and degradative capacity of lysosomes in macrophages as a novel therapeutic approach in cardiovascular disease

Award Number: R35HL183548

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2033

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer