PERM in Cardiac Function

心脏收缩需要高而可靠的ATP流量，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。都支持这一看法 氧化代谢基因突变的小鼠模型。心脏能量代谢，特别是， ATP生产的高能力是由转录调节因子网络控制的，包括 辅活化剂PGC-1 β和PGC-1 β，以及孤儿核受体ERR β和ERR β。该网络调节 对线粒体生物发生、氧化代谢和心肌细胞收缩重要的基因 （CM）。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。此类PGC-1/ERR下游效应物的阐明 可以揭示影响心脏生物能量学的新分子， 心脏能量状态在这里，我们将阐明一个新的基因，PERM 1，在心脏能量的作用， 新陈代谢.我们鉴定了它是由PGC-1 β/β和ERR β/β/β诱导的基因， 特别是在具有高能量需求的组织中，例如心脏和骨骼肌，并且在体内由 已知激活PGC-1 β的信号。我们假设PERM 1与PGC-1和ERR因子共同作用， 控制对线粒体生物发生和ATP产生重要的基因的表达， 从而保护心脏免受压力超负荷和缺血再灌注引起的心力衰竭， 损伤三个目标将检验这一假设：目标1。Perm 1调控的代谢途径研究 心肌细胞（CM）。本研究旨在研究Perm 1在培养CM中调控的代谢途径， Perm 1调节线粒体生物合成和细胞代谢途径的CM的假设。将追究 PGC-1/ERR参与Perm 1功能，并评估Perm 1 调节PGC-1/ERR活性使用定向和无偏见的方法，包括代谢组学。目标2. 确定Perm 1在压力过载诱导的HF中的作用。我们将重点讨论Perm 1在 心脏受到血液动力学应力，并评估其作用，因为心脏经历的演变， 代偿性肥大到HF。为此，我们使用小鼠模型（在手），直接CM特异性 Perm 1表达的过表达和消除（敲除（KO））-（称为Perm 1cTg和Perm 1cKO， 分别）。目标3。评价Perm 1在提供心脏保护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Perm 1在缺血性损伤中的作用 使用我们独特的小鼠模型，假设Perm 1cTG介导的过表达将被 在缺血性心脏中具有心脏保护作用，而Perm 1cKO在缺血性心脏中会产生有害反应。 挑战的心我们希望这项工作将PERM 1定义为细胞生物能量学的调节因子， 潜在地为可应用于治疗心力衰竭的治疗途径提供新的靶点。

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.