Deciphering the role of lysosomal membrane permeabilization in Diabetic Cardiac Injury

解读溶酶体膜透化在糖尿病心脏损伤中的作用

• 批准号: 10359602
• 负责人: Satoru Kobayashi
• 金额: $ 42.84万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359602
• 关键词: Address; Attenuated; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cathepsins; Cause of Death; Cell Death; Cells; Cessation of life; Cytosol; Diabetes Mellitus; Diabetic mouse; Disease; Drug Design; Enzymes; Essential worker; Extravasation; Functional disorder; Gene Targeting; Glucose; Goals; Heart; Heart Injuries; Heart failure; High Fat Diet; Homeostasis; Hyperglycemia; Injury; Lysosomes; Mediating; Mediator of activation protein; Membrane; Molecular; Monitor; Mus; Myocardial dysfunction; Organelles; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Pharmacology; Play; Quality Control; Reporter; Research; Risk; Role; Streptozocin; Stress; System; Testing; Therapeutic; Toxic effect; Transgenic Organisms; base; cell type; design; diabetic; diabetic cardiomyopathy; diabetic patient; feeding; genetic approach; heart damage; heart function; improved; innovation; insight; knock-down; novel; overexpression; prevent; repaired; response

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.

项目总结/摘要 糖尿病性心肌病和心力衰竭是糖尿病患者死亡的主要原因。然而，有效 仍然缺乏预防和管理这一致命疾病的办法。我研究的长期目标是 是为了确定介导糖尿病心脏损伤的细胞和分子机制。溶酶体起重要作用 在细胞质质量控制和细胞内稳态中的作用。最近的研究表明， 糖尿病心脏损伤和溶酶体通路紊乱之间的联系溶酶体功能障碍的一个突出特征 增加的溶酶体膜透化（LMP）引发蛋白酶渗漏和细胞死亡。我们 初步结果显示，糖尿病小鼠的心脏损伤伴随着 组织蛋白酶D（CTSD），主要的溶酶体蛋白酶。高糖诱导培养心肌细胞LMP， 导致CTSD的表达和分布改变。重要的是，CTSD过表达加剧了高表达。 葡萄糖诱导的心肌细胞死亡，而敲低CTSD或抑制CTSD活性减弱高 葡萄糖毒性我们的假设是，LMP的增加和随后的CTSD泄漏和异常 累积介导糖尿病心脏损伤;从而增强溶酶体质量控制并最小化 CTSD的异位效应将保护糖尿病心脏。我们将追求两个具体目标来检验这一假设。 目标1将确定LMP和随后的CTSD泄漏是否有助于高血糖诱导的 心肌细胞死亡目的2探讨LMP在糖尿病心脏损伤中的病理意义。 糖尿病小鼠模型。药理学和遗传学方法将用于增强溶酶体 修复和操纵CTSD的表达和成熟。糖尿病引起的溶酶体损伤将 用新的LMP报告小鼠系评估。改变CTSD对高血糖心脏毒性的影响 糖尿病性心肌病将通过多种方法来确定。顺利完成该项目 将为介导糖尿病心脏损伤的机制提供新的见解，促进药物设计， 预防或治疗糖尿病中的心肌病和心力衰竭。