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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.

摘要