# Deciphering the role of lysosomal membrane permeabilization in Diabetic Cardiac Injury

> **NIH NIH R15** · NEW YORK INST OF TECHNOLOGY · 2022 · $428,400

## Abstract

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.

## Key facts

- **NIH application ID:** 10359602
- **Project number:** 1R15HL161737-01
- **Recipient organization:** NEW YORK INST OF TECHNOLOGY
- **Principal Investigator:** Satoru Kobayashi
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $428,400
- **Award type:** 1
- **Project period:** 2022-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359602

## Citation

> US National Institutes of Health, RePORTER application 10359602, Deciphering the role of lysosomal membrane permeabilization in Diabetic Cardiac Injury (1R15HL161737-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10359602. Licensed CC0.

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