Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart

控制患病心脏心肌纤维化的信号机制

基本信息

批准号：
10075771
负责人：
Hind Lal
金额：
$ 37.13万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10075771
关键词：
Adenovirus Vector Adhesions Adult Biology Cardiac Cardiac Myocytes Cardiomyopathies Cell surface Cells Characteristics Clinical Research Couples Data Development Dilatation - action Embryo Environment Etiology Extracellular Matrix Family Fibroblasts Fibrosis Gene Targeting Glycogen Synthase Kinase 3 Goals Heart Heart Diseases Heart failure Heterodimerization Integrin beta Chains Integrins Knockout Mice Knowledge Mammals Mechanics Mediator of activation protein Mission Modeling Molecular Mus Myocardial Myocardial Infarction Myocardial Ischemia Organ Pathway interactions Phenotype Process Protein Isoforms Regulation Reporting Research Role Second Messenger Systems Signal Pathway Signal Transduction Stress Stretching Tamoxifen Testing Treatment Efficacy United States National Institutes of Health base beta catenin coronary fibrosis design glycogen synthase kinase 3 beta heart function in vivo innovation loss of function mechanotransduction mouse model new therapeutic target novel novel strategies p38 Mitogen Activated Protein Kinase periostin prevent public health relevance receptor repaired therapeutic target virtual

项目摘要

Virtually every form of progressive heart failure (HF) is associated with increased fibrosis. Currently there is no approved therapy to specifically target myocardial fibrosis in the diseased heart. Until very recently, HF studies have been largely limited to cardiomyocytes, primarily due to unavailability of cardiac fibroblast (CF)-specific mouse models. Recently, we used novel CF-specific mouse models to demonstrate that deletion of CF-GSK- 3β is detrimental in the ischemic heart. This successful utilization of CF-specific gene targeting provides a unique opportunity to further employ these newly optimized models to understand the role of CFs and their activation in myocardial disease process in vivo. The long-term goal of the proposed studies is to identify new therapeutic targets for the treatment of myocardial fibrosis and subsequent HF. Three specific aims are designed to identify the key signaling pathways and underlying primary mechanisms responsible for regulation of myocardial fibrosis. Aim 1: To elucidate the molecular mechanism by which CF-GSK-3α regulates fibrotic remodeling in the ischemic heart. The GSK-3 family consists of two isoforms, α and β. In stark contrast to our recent report with GSK-3β, our preliminary studies suggest that CF-specific deletion of GSK-3α is protective, post-MI. Based on this observation we hypothesize that CF-GSK-3α is deleterious in the process of post MI fibrotic remodeling. This hypothesis will be tested by employing CF-GSK-3α KO (periostin-cre) and tamoxifen- inducible fibroblast specific GSK-3α KO (TCF21-cre) mouse models. Aim 2: To define the molecular mechanisms by which CF-specific deletion of GSK-3β leads to adverse myocardial fibrosis. We hypothesize that GSK-3β, SMAD-3 and β-catenin function as an integrated central profibrotic signaling cascade. We will cross our GSK-3βfl/fl mice with SMAD-3fl/fl and β-cateninfl/fl mice to determine whether inhibition of the SMAD-3 and β-catenin axis is sufficient to abolish myocardial fibrosis in GSK-3βKO mice. Aim 3: Determine the mechanisms by which Integrin α1β1 (ITGα1β1) cross-talks with the profibrotic SMAD-3 and p38 pathways and identify the role of this interaction in regulation of myocardial fibrosis. Our preliminary data suggest that mechanical stretch couples to SMAD-3 activation even in the absence of TGF-β1 treatment. The predominant integrin expressed in CFs is ITGα1β1. In this aim, we will test the hypothesis that ITGα1β1 negatively regulates the TGF-β1/SMAD-3 and p38 pathways and thus exerts a critical break on myocardial fibrotic remodeling. The proposed approach is innovative, because it departs from status quo by utilizing novel CF- specific loss of function mouse models and isolated cells from them to understand the molecular mechanism of myocardial fibrosis in diseased heart. New research horizons are expected to become attainable as a result. The proposed research is highly significant, since it proposes novel strategies to prevent fibrotic remodeling in diseased heart.

事实上，每种形式的进行性心力衰竭（HF）都与纤维化增加有关，目前还没有这种情况。直到最近，心力衰竭研究才被批准用于专门针对患病心脏的心肌纤维化。主要限于心肌细胞，主要是由于缺乏心脏成纤维细胞（CF）特异性最近，我们使用新型 CF 特异性小鼠模型来证明 CF-GSK- 的缺失。 3β 是缺血性心脏的痛苦，CF 特异性基因靶向的成功利用提供了一种方法。进一步利用这些新优化的模型来了解 CF 的作用及其作用的独特机会所提出的研究的长期目标是确定新的激活在体内心肌疾病过程中的作用。治疗心肌纤维化和随后的心力衰竭的三个具体目标是。旨在确定负责调节的关键信号通路和潜在的主要机制目的 1：阐明 CF-GSK-3α 调节纤维化的分子机制。 GSK-3 家族由 α 和 β 两种异构体组成。最近关于 GSK-3β 的报告，我们的初步研究表明 CF 特异性删除 GSK-3α 具有保护作用，基于这一观察，我们发现 CF-GSK-3α 在 MI 后的过程中是有害的。该假设将通过 CF-GSK-3α KO (periostin-cre) 和他莫昔芬-进行检验。诱导成纤维细胞特异性 GSK-3α KO (TCF21-cre) 小鼠模型目标 2：定义分子模型。 CF 特异性缺失 GSK-3β 导致不良心肌纤维化的机制。 GSK-3β、SMAD-3 和 β-连环蛋白作为整合的中央促纤维化信号级联发挥作用。将 GSK-3βfl/fl 小鼠与 SMAD-3fl/fl 和 β-cateninfl/fl 小鼠杂交，以确定是否抑制 SMAD-3 β-连环蛋白轴足以消除 GSK-3βKO 小鼠的心肌纤维化。目标 3：确定整合素 α1β1 (ITGα1β1) 与促纤维化 SMAD-3 和 p38 通路相互作用的机制我们的初步数据表明，这种相互作用在调节心肌纤维化中的作用。即使没有 TGF-β1 治疗，机械拉伸也会激活 SMAD-3。 CF 中表达的整合素是 ITGα1β1。为此，我们将检验 ITGα1β1 呈阴性的假设。调节 TGF-β1/SMAD-3 和 p38 通路，从而对心肌纤维化发挥关键作用所提出的方法是创新的，因为它利用新颖的 CF- 来摆脱现状。特定功能丧失小鼠模型并从中分离细胞以了解其分子机制患病心脏的心肌纤维化有望由此实现。这项研究非常重要，因为它提出了预防纤维化重塑的新策略患病的心脏。