PERM in Cardiac Function

PERM 对心脏功能的影响

• 批准号: 10542828
• 负责人: Yoshitake Cho
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542828
• 关键词: Ablation; Acceleration; Address; Age; Animal Model; Biochemical; Bioenergetics; Biogenesis; Biology; Breeding; Cardiac; Cardiac Myocytes; Cell Respiration; Chronic; Compensation; Complex; Coronary; Data; Development; Dilated Cardiomyopathy; Disease; ERR1 protein; Energy Metabolism; Evolution; Future; Gene Expression; Genes; Genetic Transcription; Hand; Heart; Heart Diseases; 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; Nuclear Orphan Receptor; Organism; 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; aorta constriction; cardioprotection; 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

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-1α and PGC-1β, and the orphan nuclear receptors ERRα and ERRγ. 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-1α/β and ERRα/β/γ 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-1α. 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.

心脏收缩需要高而可靠的三磷酸腺苷流量，因为能量缺乏会导致疾病，如图所示 在线粒体DNA或核编码呼吸基因突变的人类中。这是由支持的 氧化代谢基因突变的小鼠模型。心脏能量代谢，尤其是， ATP的高生产能力由转录调控网络控制，包括 辅活化子pGC-1α和pGC-1β，以及孤儿核受体Errα和Errγ。这个网络规范着 线粒体生物发生、氧化代谢和心肌细胞收缩的重要基因 (厘米)。PGC-1/ERR复合体不仅直接作用于许多靶基因，而且还激活下游转录 扩大和/或扩大其行动范围的因素。PGC-1/ERR下游效应因子的研究进展 可以揭示影响心脏生物能量学的新分子，并可用于有益地修改 心脏能量状态。在这里，我们将阐明一种新的基因PERM1在心脏能量中的作用 新陈代谢。我们鉴定它是由pGC-1α/β和ERRα/β/γ诱导的一个基因，并发现它表达 特别是在具有高能量需求的组织中，如心脏和骨骼肌，并在体内由 已知的激活pGC-1α的信号。我们假设PERM1与PGC-1和ERR因子一起作用于 控制对线粒体生物发生和ATP生产至关重要的基因的表达， 从而保护心脏免受压力超负荷和缺血再灌流引起的心力衰竭 受伤。三个目标将验证这一假说：目标1.Perm1调节的代谢途径的研究 心肌细胞(CM)。本研究的目的是研究Perm1在培养的CM中调节的代谢途径，以评估 Perm1在CM中调节有丝分裂生物发生和细胞代谢途径的假说。它将继续追查 PGC-1/ERR在Perm1功能中的作用及其机制探讨(S) 使用定向和无偏见的方法，包括代谢组学，调节PGC-1/ERR的活性。目标2. 确定Perm1在压力超负荷诱导的心衰中的作用。我们将重点介绍Perm1在 心脏受到血流动力学应激，并评估其在心脏经历从 代偿性肥大转为心衰。为此，我们使用鼠标模型(在手中)，它指示特定于CM的 Perm1表达的过表达和消融(敲除(KO))-(称为Perm1cTg和Perm1cKO， )。目的3.评价Perm1在保护心脏免受有害影响方面的作用 缺血和缺血-再灌流(IR)损伤。我们还将研究Perm1在缺血损伤中的作用 使用我们独特的小鼠模型，假设Perm1cTG介导的过度表达将是 Perm1cKO在缺血心脏中具有心脏保护作用，而Perm1cKO在缺血心脏中会产生有害反应。 挑战的心脏。我们希望这项工作将PERM1定义为细胞生物能量学的调节因子，并 有可能为治疗心力衰竭的治疗途径提供一个新的靶点。

项目成果

Metabolic Flexibility of the Heart: The Role of Fatty Acid Metabolism in Health, Heart Failure, and Cardiometabolic Diseases.

• DOI: 10.3390/ijms25021211
• 发表时间: 2024-01-19
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.

• DOI: 10.1016/j.jbc.2021.100825
• 发表时间: 2021-07
• 期刊: The Journal of biological chemistry
• 作者: Cho Y;Tachibana S;Lam K;Arita Y;Khosrowjerdi S;Zhang O;Liang A;Li R;Andreyev A;Murphy AN;Ross RS
• 通讯作者: Ross RS