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Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response

通过模仿适应性肝葡萄糖空腹反应来治疗继发性心肌病

基本信息

批准号：
10627917
负责人：
Brian Jesse DeBosch
金额：
$ 62.65万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627917
关键词：
Attenuated Autophagocytosis Caloric Restriction Cardiac Cardiac Myocytes Cardiometabolic Disease Cardiomyopathies Cardiovascular system Catabolism Chronic Clinical Clinical Trials Data Disaccharides Disease Disease model FGF21 gene Fasting Fatty Liver Functional disorder Gene Expression Glucose Transporter Goals Growth Growth Factor Receptors Heart Diseases Heart failure Hepatic Hepatocyte Hormone secretion Human Hypertrophy Infarction Insulin Resistance Intermittent fasting Ischemia Laboratories Left Ventricular Hypertrophy Light Liver Metabolism Modeling Mus Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Injury Myocardial dysfunction Myocardium Nutraceutical Oral Pathologic Pathway interactions Patients Publishing Reagent Receptor Signaling Reperfusion Injury Reperfusion Therapy Resistance Rodent Secondary Myocardial Diseases Signal Transduction Stimulus Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Trehalose Work analog aorta constriction cardioprotection cardiovascular risk factor clinically relevant efficacy evaluation fasting glucose fibroblast growth factor 21 genetic approach glucose metabolism glucose transport improved inhibitor innovation microbial mimetics mortality mouse genetics mouse model next generation novel novel therapeutics peptide hormone pharmacologic pressure prevent response small molecule tool

项目摘要

ABSTRACT Intermittent fasting and caloric restriction are newly identified therapeutic interventions against cardiometabolic disease. Our laboratory discovered that activating the hepatic glucose fasting response is sufficient to convey several of the key therapeutic effects of generalized caloric restriction. This is clinically relevant because targeting hepatic glucose transport is highly amenable to small-molecule and nutraceutical therapy. Therefore, our long-term goal is to understand adaptive liver glucose metabolism during fasting to produce new therapies that leverage these pathways against cardiometabolic disease. Intermittent fasting in rodents blocks pathological remodeling and infarct expansion after myocardial infarction, and treating mice with FGF21 – a liver-derived peptide hormone secreted in response to fasting – prevents experimental cardiac left ventricular hypertrophy (LVH) and LV dysfunction. We demonstrated that blocking hepatic glucose transport using the naturally occurring disaccharide, trehalose, recapitulates the hepatic adaptive fasting response. Our new data now demonstrate that oral trehalose recapitulates the effects of intermittent fasting on cardiac protection against pathological remodeling. Specifically, trehalose induces hepatic FGF21, and prevents pathological LVH and LV dysfunction in response to chronic pressure overload. We also identified a novel trehalose analog that resists degradation by host and microbial metabolism, and which activates hepatic fasting-like signal transduction to a greater extent than native trehalose. This study’s objective is thus to define mechanisms and contexts of cardioprotection by trehalose-class compounds as a prelude to the use of these compounds in human trials. Our central hypothesis is that hepatic GLUT inhibition blocks LVH and LVD by activating canonical hepatic fasting signals to the myocardium. We propose three Specific Aims to test this hypothesis. In Aim 1, we will delineate mechanisms by which trehalose prevents LVH and LVD. In Aim 2, we define pathophysiological contexts in which trehalose attenuates secondary cardiomyopathies. In Aim 3, we examine the impact of trehalose catabolism on its efficacy against secondary cardiomyopathies. The innovation of this proposal is that we our team has identified and will examine further: 1) a novel and tractable cardioprotective pathway, and 2) a novel compound class that activates this cardioprotective pathway. Completing these aims will define how hepatocyte fasting responses protect from pathological remodeling and dysfunction; and nominate specific clinical contexts in which the adaptive hepatic fasting response is cardioprotective. The impact of this work is that it will mechanistically inform next-generation glucose fasting- mimetics, which also leverage the adaptive fasting response against cardiac disease, and will justify further efforts toward clinical trials that utilize trehalose-class compounds to ameliorate secondary cardiomyopathies.

抽象的间歇性禁食和热量限制是新确定的针对心脏代谢的治疗干预措施疾病。我们的实验室发现激活肝脏葡萄糖空腹反应足以传达全面热量限制的几个关键治疗效果。这在临床上是相关的，因为以肝脏葡萄糖转运为目标的药物非常适合小分子和营养治疗。所以，我们的长期目标是了解禁食期间的适应性肝脏葡萄糖代谢，以产生新的疗法利用这些途径对抗心脏代谢疾病。啮齿类动物的间歇性禁食可阻止心肌梗塞后的病理重塑和梗塞扩张，用 FGF21（一种因禁食而分泌的肝源性肽激素）治疗小鼠可预防实验性心脏左心室肥厚（LVH）和左心室功能障碍。我们证明了阻塞使用天然存在的二糖海藻糖进行肝脏葡萄糖转运，概括了肝脏适应性禁食反应。我们的新数据现在证明口服海藻糖重现了以下效果：间歇性禁食对心脏防止病理重塑的保护作用。具体来说，海藻糖会诱导肝 FGF21，并预防慢性压力超负荷引起的病理性 LVH 和 LV 功能障碍。我们也发现了一种新型海藻糖类似物，可以抵抗宿主和微生物代谢的降解，并且比天然海藻糖更大程度地激活肝脏禁食样信号转导。本研究的目的因此，我们的任务是定义海藻糖类化合物的心脏保护机制和背景，以此作为前奏这些化合物在人体试验中的使用。我们的中心假设是肝脏过量抑制可阻断 LVH 通过激活向心肌传递的规范肝脏禁食信号来实现 LVD。我们提出三个具体目标来检验这一假设。在目标 1 中，我们将描述机制海藻糖可预防 LVH 和 LVD。在目标 2 中，我们定义了海藻糖减弱的病理生理学背景继发性心肌病。在目标 3 中，我们研究了海藻糖分解代谢对其功效的影响继发性心肌病。该提案的创新之处在于，我们的团队已经确定并将进一步研究：1）一种新颖且易处理的心脏保护途径，2) 一种激活该心脏保护途径的新型化合物类别。完成这些目标将确定肝细胞禁食反应如何防止病理重塑和功能障碍；并指定适应性肝禁食反应的具体临床背景心脏保护作用。这项工作的影响在于，它将机械地为下一代葡萄糖禁食提供信息—— 模拟物，它还利用适应性禁食反应来对抗心脏病，并将进一步证明其合理性致力于利用海藻糖类化合物改善继发性心肌病的临床试验。