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针对心脏代谢的新鉴定的治疗干预措施疾病。我们的实验室发现，激活肝葡萄糖禁食反应足以传达广义热限制的几种关键治疗效应。这在临床上是相关的，因为靶向肝葡萄糖转运非常适合小分子和营养疗法。所以，我们的长期目标是在禁食期间了解自适应肝葡萄糖代谢以产生新的疗法这利用这些途径抵抗心脏代谢疾病。啮齿动物中的间歇性禁食阻止心肌梗塞后的病理重塑和梗塞扩张，并用FGF21治疗小鼠 - 响应禁食的肝脏衍生的肽马酮 - 可防止实验性心脏左心室肥大（LVH）和LV功能障碍。我们证明了阻止使用天然存在的二糖，海毛糖的肝葡萄糖转运，概括了hepati 自适应禁食响应。现在，我们的新数据表明，口服海藻糖概括了心脏保护避免病理重塑的间歇性禁食。具体而言，海藻糖诱导肝 FGF21，并防止病理LVH和LV功能障碍响应慢性压力超负荷。我们也是确定了一种新型的海藻糖类似物，该类似物抵抗了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禁食的信号转移。这项研究的目标因此，是通过海藻糖级化合物来定义心脏保护的机制和上下文在人类试验中使用这些化合物。我们的中心假设是肝脏间隙抑制阻滞LVH 和LVD通过向心肌激活规范的肝禁食信号。我们提出了三个特定的目的来检验这一假设。在AIM 1中，我们将描述通过的机制海藻糖可防止LVH和LVD。在AIM 2中，我们定义了海藻糖减弱的病理生理环境继发性心肌病。在AIM 3中，我们研究了海藻糖分解代谢对其有效性的影响继发性心肌病。该提议的创新是我们团队已经确定并将进一步研究：1）小说和可处理的心脏保护途径，以及2）一种激活此心脏保护途径的新型化合物。完成这些目标将定义肝细胞禁食反应如何防止病理重塑和功能障碍；并提名自适应肝禁食反应的特定临床环境是心脏保护。这项工作的影响是，它将机械地告知下一代葡萄糖空腹 - Mimetics，还利用了针对心脏病的自适应禁食反应，并将进一步证明临床试验的努力，利用海藻糖级化合物改善继发性心肌病。