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Deciphering the role of lysosomal membrane permeabilization in Diabetic Cardiac Injury

Award Number: R15HL161737
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Deciphering the role of lysosomal membrane permeabilization in Diabetic Cardiac Injury - PROJECT SUMMARY/ABSTRACT Diabetic cardiomyopathy and heart failure are a leading cause of death in diabetic patients. However, effective approaches to preventing and managing this deadly disease are still lacking. The long-term goal of my research is to identify cellular and molecular mechanisms that mediate diabetic cardiac injury. Lysosomes play important roles in cytoplasmic quality control and cellular homeostasis. Recent studies have demonstrated an association between diabetic cardiac injury and a disturbed lysosome pathway. A prominent feature of lysosomal dysfunction is increased lysosomal membrane permeabilization (LMP) which triggers protease leakage and cell death. Our preliminary results showed that cardiac damage in diabetic mice was accompanied by elevated expression of cathepsin D (CTSD), a major lysosomal protease. High glucose induced LMP in cultured cardiomyocytes, leading to altered expression and distribution of CTSD. Importantly, CTSD overexpression exacerbated high glucose-induced cardiomyocyte death, while knocking down CTSD or inhibiting CTSD activity attenuated high glucose toxicity. Our hypothesis is that the increased LMP and the ensuing CTSD leakage and aberrant accumulation mediate diabetic cardiac injury; thus enhancing lysosomal quality control and minimizing the ectopic effects of CTSD will protect the diabetic heart. We will pursue two specific aims to test this hypothesis. Aim 1 will determine whether LMP and the ensuing CTSD leakage contributes to hyperglycemia-induced cardiomyocyte death. Aim 2 will investigate the pathological significance of LMP in diabetic heart injury using mouse models of diabetes. Pharmacological and genetic approaches will be used to enhance the lysosomal repair and to manipulate the expression and maturation of CTSD. Diabetes-induced lysosomal injury will be assessed with a novel LMP reporter mouse line. The effects of altered CTSD on hyperglycemic cardiotoxicity and diabetic cardiomyopathy will be determined with multiple approaches. Successful completion of this project will provide novel insight into the mechanisms that mediate diabetic cardiac injury, facilitating drug design for preventing or treating cardiomyopathy and heart failure in diabetes.


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 = $0 )
2025	2022	NEW YORK INSTITUTE OF TECHNOLOGY	1855 BROADWAY	NEW YORK	NY	10023	NEW YORK	USA	Cardiovascular Diseases Research	000	1	2/28/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $428,400 )
2022	2022	NEW YORK INSTITUTE OF TECHNOLOGY	NORTHERN BLVD	OLD WESTBURY	NY	11568	NASSAU	USA	Cardiovascular Diseases Research	000	1	2/7/2022	NEW	$428,400
														Subtotal = $428,400

Grand Total All Awards = $428,400

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Deciphering the role of lysosomal membrane permeabilization in Diabetic Cardiac Injury

Award Number: R15HL161737

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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