Role of LMPTP in cardiac fibrosis

LMPTP 在心脏纤维化中的作用

基本信息

批准号：
10705848
负责人：
Nunzio Bottini
金额：
$ 56.31万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2020-08-11 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705848
关键词：
Address Alternative Splicing Angiotensin II Automobile Driving Blood Pressure Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Chemicals Collagen Complex Data Deposition Depressed mood Diabetes Mellitus EFRAC Extracellular Matrix Extracellular Matrix Proteins FDA approved FRAP1 gene Failure Fibroblasts Fibrosis Functional disorder Genes Genetic Polymorphism Growth Factor Heart Heart Hypertrophy Heart failure Human Hypertrophy Impairment Infusion procedures Insulin Receptor Investigation Knock-out Knockout Mice Laboratories Liver Longevity Lung Mediating Medical Mitogen-Activated Protein Kinases Modeling Molecular Mechanisms of Action Molecular Weight Mouse Strains Mus Myocardial Myocardial Infarction Myofibroblast Obesity Pathogenesis Pathologic Pathology Pathway interactions Patients Phosphorylation Physiological Profibrotic signal Proline Protein Dephosphorylation Protein Inhibition Protein Isoforms Protein Tyrosine Phosphatase Proteins Proto-Oncogene Proteins c-akt Receptor Protein-Tyrosine Kinases Reporting Research Role Series Signal Transduction Testing Tissues Transforming Growth Factor beta Tyrosine Virulence Factors antifibrotic treatment aorta constriction cell type coronary fibrosis cytokine experience experimental study fibrogenesis genetic variant heart function in vivo inhibitor insight interest kidney cell late endosome mouse model novel phosphoproteomics preservation pressure prevent profibrotic fibroblast promoter small molecule tool transcription factor

项目摘要

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.

项目概要该提案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）在心脏纤维化中的作用。心脏纤维化是心力衰竭发病机制的主要原因。在心脏组织中，纤维化提示病理变化包括扩张和肥大，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，减轻心脏纤维化的新药是心脏病学中一个未得到满足的重大医疗需求。该提案重点关注由 ACP1 基因编码的酪氨酸磷酸酶 LMPTP。 LMPTP 有被认为是通过酪氨酸去磷酸化通过受体酪氨酸激酶信号传导的抑制剂其激活基序中的残基。在人类中，ACP1 基因的遗传多态性编码高已知 LMPTP 活性可促进心肌肥厚。我们之前报道过 LMPTP 表达在患有终末期心力衰竭的人的心脏中显着上调。我们生成了第一个 LMPTP 基因敲除小鼠发现，当通过横主动脉收缩而承受血压超负荷时（TAC），它们可以免受心脏肥大和衰竭的影响，并显着减少心脏纤维化心脏。我们还发现，我们开发的小分子化学抑制剂可以抑制 LMPTP 导致 TAC 治疗小鼠的心脏纤维化、肥大和衰竭减少。综合起来，这些发现表明 LMPTP 作为心脏纤维化和衰竭的促进者的新作用。在这里，我们提出了一系列的机制实验来阐明生理和分子 LMPTP 在纤维化相关心力衰竭中的作用机制。我们将（目标 1）证明 LMPTP 在多种小鼠模型中促进心脏纤维化，（目标 2）确定 LMPTP 促进的细胞类型心脏纤维化，以及（目标 3）确定 LMPTP 促进心脏纤维化的分子机制纤维化和衰竭。