Roles of SARM1 NAD hydrolase in metabolic cardiomyopathy

SARM1 NAD 水解酶在代谢性心肌病中的作用

• 批准号: 10733867
• 负责人: Chi Fung Lee
• 金额: $ 63.41万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733867
• 关键词: Area; Binding; Biosensor; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cell Death; Cells; Consumption; Cytosol; Data; Disease; Functional disorder; Future; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Hydrolase; Insulin-Dependent Diabetes Mellitus; Knockout Mice; Link; MAPK8 gene; Measures; Mediating; Metabolic; Metabolic Activation; Metabolic stress; Mitochondria; Mitochondrial Proteins; Modeling; Mus; Neurons; Niacinamide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outer Mitochondrial Membrane; PINK1 gene; Parkin; Pathogenicity; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Proteins; Proteome; Recycling; Reporting; Research; Role; Signal Transduction; Sterility; Stress; Stress cardiomyopathy; Therapeutic; Transcript; axon injury; axonal degeneration; cardioprotection; desensitization; diabetes control; diabetic; diabetic cardiomyopathy; diet-induced obesity; heart function; inhibitor; metabolome; mitochondrial dysfunction; mitochondrial permeability transition pore; multiple omics; neuron loss; new therapeutic target; pharmacologic; prevent; protein biomarkers; recruit; therapeutic development; transcriptome

NAD+ depletion is observed in diseases including heart failure and metabolic cardiomyopathy. Maintaining NAD+ homeostasis by activating NAD+ synthesis pathways has shown great promise to treat diseases. We here explore that inhibiting NAD+ consumption will prevent NAD+ depletion and ameliorate heart disease. NAD+ hydrolases catalyze NAD+ degradation to form nicotinamide and ADPR. SARM1 is an intracellular NAD+ hydrolase that is known as an executer of axonal degeneration and promotes mitochondrial dysfunction. Recent studies showed that SARM1 is activated by increased NMN/NAD+ ratio and SARM1 phosphorylation. However, the role of SARM1 in metabolic cardiomyopathy has never been reported, and how SARM1 is activated to cause mitochondrial dysfunction is not known. The overall objective of this project is to investigate how SARM1 promotes NAD+ decline and regulates mitophagy during metabolic cardiomyopathy. Further understanding of SARM1 in the heart will lead to a new target for therapeutic development of heart disease. In our pilot data, we showed that SARM1 deficiency in SARM1-KO mice and in newly developed cardiomyocyte-specific SARM1-KO mice (SARM1-cKO) protected against metabolic stress-induced cardiomyopathy, providing the first evidence on the role of SARM1 in causing dysfunction of diabetic hearts. Pilot data further suggested that NAD+ metabolic and JNK1 phosphorylation signaling may activate SARM1, and SARM1 promotes mitophagy in diabetic hearts. Based on these results, we propose to dissect the pathogenic mechanisms of SARM1 in metabolic cardiomyopathy with the three aims. Specific Aim 1 will use SARM1-cKO mice to determine the impact of cardiomyocyte SARM1 deficiency on type 1 diabetes (T1D)- induced and diet-induced obesity (DIO)-induced cardiomyopathy. Multi-omics analyses targeting known mechanistic pathways of diabetic hearts will be performed to identify how cardiomyocyte SARM1 deficiency protects hearts against the two types of metabolic stresses. Specific Aim 2 will understand how metabolic stress activates SARM1 to cause compartmental NAD+ decline. We will manipulate NAD+ metabolic and JNK1- SARM1 phosphorylation signaling to establish how the two pathways activate SARM1 to cause NAD+ decline in mitochondria or cytosol using compartment-specific NAD+ biosensors. Specific Aim 3 will determine how SARM1 promotes mitophagy in diabetic hearts. Mitophagy flux impacted by metabolic stress and SARM1 deficiency will be measured by mito-Keima mice. How SARM1 promotes mitophagy via traditional PINK1- Parkin and/or alternative Ulk1-Rab9 pathways will be examined in diabetic hearts. This project will establish SARM1 as a new target to promote NAD+ decline mitochondrial dysfunction and metabolic cardiomyopathy. The results from this project will identify new therapeutic targets linked to SARM1-dependent mechanisms.

NAD+ 耗竭可在心力衰竭和代谢性心肌病等疾病中观察到。维护 通过激活 NAD+ 合成途径实现 NAD+ 稳态已显示出治疗疾病的巨大前景。我们 本文探讨抑制 NAD+ 消耗将防止 NAD+ 消耗并改善心脏病。辅酶A+ 水解酶催化 NAD+ 降解形成烟酰胺和 ADPR。 SARM1 是一种细胞内 NAD+ 水解酶被称为轴突变性的执行者并促进线粒体功能障碍。 最近的研究表明，NMN/NAD+ 比率增加和 SARM1 磷酸化可激活 SARM1。 然而，SARM1在代谢性心肌病中的作用从未有报道，而SARM1是如何发挥作用的呢？ 激活导致线粒体功能障碍尚不清楚。该项目的总体目标是调查 SARM1 如何促进 NAD+ 下降并在代谢性心肌病期间调节线粒体自噬。更远 对心脏中 SARM1 的了解将为心脏病的治疗开发提供新的靶点。 在我们的试验数据中，我们表明 SARM1-KO 小鼠和新开发的小鼠中存在 SARM1 缺陷 心肌细胞特异性 SARM1-KO 小鼠 (SARM1-cKO) 免受代谢应激诱导 心肌病，为 SARM1 在导致糖尿病心脏功能障碍中的作用提供了第一个证据。 试验数据进一步表明 NAD+ 代谢和 JNK1 磷酸化信号可能激活 SARM1， SARM1 促进糖尿病心脏的线粒体自噬。基于这些结果，我们建议剖析 SARM1在代谢性心肌病中的致病机制具有三个目的。具体目标 1 将使用 SARM1-cKO 小鼠确定心肌细胞 SARM1 缺陷对 1 型糖尿病 (T1D) 的影响 - 诱发和饮食诱发的肥胖（DIO）诱发的心肌病。针对已知的多组学分析 将研究糖尿病心脏的机制途径，以确定心肌细胞 SARM1 缺陷如何发生 保护心脏免受两种类型的代谢应激。具体目标 2 将了解新陈代谢如何 压力激活 SARM1 导致区室 NAD+ 下降。我们将操纵 NAD+ 代谢和 JNK1- SARM1 磷酸化信号传导，以确定两条途径如何激活 SARM1 导致 NAD+ 下降 使用隔室特异性 NAD+ 生物传感器在线粒体或细胞质中进行检测。具体目标 3 将决定如何 SARM1 促进糖尿病心脏的线粒体自噬。代谢应激和 SARM1 影响的线粒体自噬通量 缺陷将通过 mito-Keima 小鼠进行测量。 SARM1 如何通过传统 PINK1 促进线粒体自噬 将在糖尿病心脏中检查 Parkin 和/或替代 Ulk1-Rab9 通路。该项目将建立 SARM1作为促进NAD+下降线粒体功能障碍和代谢性心肌病的新靶点。 该项目的结果将确定与 SARM1 依赖性机制相关的新治疗靶点。