Role of LMPTP in cardiac fibrosis

项目总结 这项建议的目的是确定低分子量蛋白质的作用机制。 酪氨酸磷酸酶(LMPTP)与心肌纤维化 心脏纤维化是心力衰竭发病机制的主要因素。在心脏组织中，纤维化提示 包括扩张和肥大在内的病理变化，最终导致心力衰竭。没有 FDA批准的治疗心力衰竭的抗纤维化药物；因此，缓解心脏纤维化的新药是 这是心脏病学尚未得到满足的主要医疗需求。 这项建议的重点是酪氨酸磷酸酶LMPTP，它由ACP1基因编码。LMPTP具有 被认为是一种通过酪氨酸去磷酸化受体酪氨酸激酶的信号抑制物 它们的激活模体中的残基。在人类中，编码高密度脂蛋白的ACP1基因的遗传多态性 众所周知，LMPTP活性可促进心肌肥厚。我们之前报道过LMPTP的表达 在终末期心力衰竭患者的心脏中显著上调。我们生成了第一个LMPTP 基因敲除的小鼠发现，当受到血压超负荷时，通过横向主动脉收缩 (TAC)，它们可防止心肌肥大和衰竭，并在 心脏。我们还发现，用我们开发的一种小分子化学抑制剂来抑制LMPTP 导致TAC治疗的小鼠减少心脏纤维化、肥大和衰竭。综上所述，这些发现 提示LMPTP作为心脏纤维化和衰竭的促进剂具有新的作用。 在这里，我们提出了一系列的机制实验来阐明生理和分子方面的。 LMPTP在纤维化相关性心力衰竭中的作用机制。我们将(目标1)演示LMPTP 在多种小鼠模型中促进心脏纤维化，(目标2)确定LMPTP促进心肌纤维化的细胞类型 目的3)确定LMPTP促进心脏功能的分子机制。 纤维化和衰竭。

PROJECT SUMMARY The objective of this proposal is to determine the mechanism of action of the low molecular weight protein tyrosine phosphatase (LMPTP) in cardiac fibrosis. Cardiac fibrosis is a major contributor to the pathogenesis of heart failure. In cardiac tissue, fibrosis prompts pathological changes that include dilation and hypertrophy, and ultimately leads to heart failure. There are no FDA-approved anti-fibrotic medications for heart failure; therefore, novel agents to alleviate cardiac fibrosis are a major unmet medical need in cardiology. This proposal focuses on the tyrosine phosphatase LMPTP, which is encoded by the ACP1 gene. LMPTP has been considered an inhibitor of signaling through receptor tyrosine kinases by dephosphorylation of tyrosine residues in their activation motifs. In humans, genetic polymorphisms in the ACP1 gene encoding for high LMPTP activity are known to promote myocardial hypertrophy. We previously reported that LMPTP expression is significantly upregulated in hearts of humans with end-stage heart failure. We generated the first LMPTP knockout mice and found that when subjected to blood pressure overload through transverse aortic constriction (TAC), they are protected from cardiac hypertrophy and failure, and develop substantially decreased fibrosis in the heart. We also found that inhibiting LMPTP with a small-molecule chemical inhibitor that we developed leads to reduced cardiac fibrosis, hypertrophy, and failure in TAC-treated mice. Taken together, these findings suggest a novel role for LMPTP as a promoter of cardiac fibrosis and failure. Here we propose a series of mechanistic experiments to elucidate the physiological and molecular mechanisms of action of LMPTP in fibrosis-associated heart failure. We will (Aim 1) demonstrate that LMPTP promotes cardiac fibrosis in multiple mouse models, (Aim 2) determine the cell type by which LMPTP promotes cardiac fibrosis, and (Aim 3) determine the molecular mechanism of action of LMPTP in promoting cardiac fibrosis and failure.