权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

PERM in Cardiac Function

PERM 对心脏功能的影响

基本信息

批准号：
9917489
负责人：
Yoshitake Cho
金额：
$ 39.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917489
关键词：
Ablation Address Age Animal Model Biochemical Bioenergetics Biogenesis Biology Breeding Cardiac Cardiac Myocytes Cell Respiration Chronic Complex Coronary Data Development Dilated Cardiomyopathy Disease ERR1 protein Energy Metabolism Estrogen Nuclear Receptor Evolution Future Gene Expression Genes Genetic Transcription Hand Heart Heart Diseases Heart Mitochondria Heart failure Human Hypertrophy Ischemia Knock-out Lead Learning Ligation Mediating Metabolic Metabolic Pathway Metabolism Microscopy Mitochondria Mitochondrial DNA Modeling Molecular Morbidity - disease rate Mus Muscle Muscle Fibers Muscle function Mutation Myocardial Myocardial Infarction Myocardial Ischemia Myocardium Nuclear Organism Orphan Oxygen PPAR gamma Pathway interactions Patients Physiological Physiology Play Production Proteins Publishing Receptor Signaling Regulation Reperfusion Injury Reperfusion Therapy Role Signal Transduction Skeletal Muscle Stress Striated Muscles Testing Tissues Transgenic Organisms Work base cardiogenesis cardioprotection constriction emerging adult estrogen-related receptor genome-wide analysis heart function heart metabolism hemodynamics human model improved in vivo innovation ischemic cardiomyopathy ischemic injury metabolic abnormality assessment metabolomics mitochondrial dysfunction mortality mouse model muscle metabolism myocardial damage new therapeutic target novel novel strategies novel therapeutics overexpression oxidative damage pressure prevent reduce symptoms respiratory response transcription factor

项目摘要

Cardiac contraction requires a high and reliable flux of ATP as energetic deficiencies lead to disease, as seen in humans with mutations in mitochondrial DNA or nuclear-encoded respiratory genes. This is supported by mouse models with mutations in genes of oxidative metabolism. Cardiac energy metabolism and, in particular, the high capacity for ATP production are controlled by a network of transcriptional regulators, including the coactivators PGC-1 and PGC-1, and the orphan nuclear receptors ERR and ERR. This network regulates genes important for mitochondrial biogenesis, oxidative metabolism and thus contraction of cardiac myocytes (CM). PGC-1/ ERR complexes act directly on many target genes, but also activate downstream transcription factors that amplify and/or extend their scope of action. Elucidation of such PGC-1/ERR downstream effectors can reveal novel molecules that impact heart bioenergetics and that could be used to beneficially modify cardiac energy state. Here, we will elucidate the role of a novel gene, PERM1, in cardiac energy metabolism. We identified it as a gene induced by PGC-1/ and ERR//and found it expressed specifically in tissues with high-energy demand, such as heart and skeletal muscle, and induced in vivo by signals known to activate PGC-1. We hypothesize that PERM1 acts with PGC-1 and ERR factors in controlling the expression of genes important for mitochondrial biogenesis and ATP production, thereby protecting the heart from heart failure induced by pressure overload and ischemia reperfusion injury. Three aims will test this hypothesis: Aim 1. Study of the metabolic pathways regulated by Perm1 in cardiomyocytes (CM). This aim will study metabolic pathways regulated by Perm1 in cultured CM to evaluate the hypothesis that Perm1 modulates Mito biogenesis and cellular metabolic pathways in the CM. It will pursue the involvement of PGC-1/ERR in Perm1 function, and also evaluate mechanism(s) by which Perm1 modulates PGC-1/ERR activity using directed and unbiased approaches, including metabolomics. Aim 2. Determine the role of Perm1 in pressure overload-induced HF. We will focus on the role of Perm1 in the heart subjected to hemodynamic stress, and assess its role as the heart undergoes evolution from compensated hypertrophy to HF. For this we use mouse models (in hand) which direct CM-specific overexpression and ablation (knockout (KO)) of Perm1 expression – (termed Perm1cTg and Perm1cKO, respectively). Aim 3. Evaluate the role of Perm1 in providing cardiac protection from deleterious effects of ischemia and ischemia-reperfusion (IR) injury. We will study the role of Perm1 in ischemic injury also using our unique mouse models, given the hypothesis that Perm1cTG-mediated overexpression will be cardioprotective in the ischemic heart, while Perm1cKO will produce deleterious responses in ischemic- challenged hearts. We expect this work to define PERM1 as a regulator of cellular bioenergetics and potentially provide a new target for therapeutic pathways that are applicable to treatment of heart failure.

心脏收缩需要高且可靠的 ATP 通量，因为能量不足会导致疾病，如图所示线粒体 DNA 或核编码呼吸基因突变的人类。这得到了支持氧化代谢基因突变的小鼠模型。心脏能量代谢，特别是 ATP 的高生产能力由转录调节因子网络控制，包括共激活因子 PGC-1 和 PGC-1，以及孤儿核受体 ERR 和 ERR。该网络监管对线粒体生物发生、氧化代谢以及心肌细胞收缩很重要的基因（厘米）。 PGC-1/ ERR 复合物直接作用于许多靶基因，但也激活下游转录扩大和/或扩大其行动范围的因素。阐明此类 PGC-1/ERR 下游效应子可以揭示影响心脏生物能学的新分子，并可用于有益地改变心脏能量状态。在这里，我们将阐明一个新基因 PERM1 在心脏能量中的作用代谢。我们将其鉴定为由PGC-1α/β和ERRα/β/α诱导的基因，并发现其表达特别是在具有高能量需求的组织中，例如心脏和骨骼肌，并在体内诱导已知激活 PGC-1α 的信号。我们假设 PERM1 与 PGC-1 和 ERR 因子一起作用控制对线粒体生物发生和 ATP 产生重要的基因表达，从而保护心脏免受压力超负荷和缺血再灌注引起的心力衰竭受伤。三个目标将检验这一假设：目标 1. 研究 Perm1 调控的代谢途径心肌细胞（CM）。该目标将研究培养 CM 中 Perm1 调节的代谢途径，以评估 Perm1 调节 CM 中 Mito 生物发生和细胞代谢途径的假设。它将追求 PGC-1/ERR 在 Perm1 功能中的参与，并评估 Perm1 的机制使用定向和公正的方法（包括代谢组学）调节 PGC-1/ERR 活性。目标2。确定 Perm1 在压力过载引起的 HF 中的作用。我们将重点关注 Perm1 在心脏承受血流动力学压力，并评估其在心脏经历进化过程中的作用 HF 的代偿性肥大。为此，我们使用鼠标模型（手持）来指导 CM 特定的 Perm1 表达的过度表达和消除（敲除 (KO)）——（称为 Perm1cTg 和 Perm1cKO，分别）。目标 3. 评估 Perm1 在保护心脏免受有害影响方面的作用缺血和缺血再灌注（IR）损伤。我们还将研究Perm1在缺血性损伤中的作用使用我们独特的小鼠模型，假设 Perm1cTG 介导的过度表达将对缺血性心脏具有心脏保护作用，而 Perm1cKO 会在缺血性心脏中产生有害反应挑战的心。我们期望这项工作将 PERM1 定义为细胞生物能量学的调节剂，可能为适用于心力衰竭治疗的治疗途径提供新的靶点。