Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart

控制患病心脏心肌纤维化的信号机制

• 批准号: 10163250
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163250
• 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; 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; therapeutically effective; virtual

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.

实际上，每种形式的进行性心力衰竭（HF）都与纤维化增加有关。目前没有 经过批准的疗法，专门靶向解剖心脏中的心肌纤维化。直到最近，HF研究 由于心脏成纤维细胞不可用（CF）特异性 鼠标模型。最近，我们使用了新颖的CF特异性小鼠模型来证明CF-GSK-的缺失 3β在缺血性心脏中有害。 CF特异性基因靶向的成功利用提供了 独特的机会来进一步员工这些新优化的模型，以了解CFS及其作用 体内心肌疾病过程中的激活。拟议研究的长期目标是确定新的 治疗心肌纤维化和随后的HF的治疗靶标。三个具体目标是 旨在确定关键信号通路和负责调节的主要机制 心肌纤维化。目标1：阐明CF-GSK-3α调节纤维化的分子机制 在缺血性心脏中重塑。 GSK-3家族由两个同工型α和β组成。与我们形成鲜明对比 GSK-3β的最新报告，我们的初步研究表明，GSK-3α的CF特异性缺失受到保护，受到保护， 后。基于此观察，我们假设CF-GSK-3α在MI后的过程中是有害的 纤维化重塑。该假设将通过使用CF-GSK-3αKO（骨膜蛋白-CRE）和他莫昔芬 - 诱导型成纤维细胞特异性GSK-3αKO（TCF21-CRE）小鼠模型。目标2：定义分子 GSK-3β的CF特异性缺失导致心肌纤维化的机制。我们假设 GSK-3β，SMAD-3和β-catenin充当集成的中央纤维化信号级联。我们将 用SMAD-3FL/FL和β-Cateninfl/FL小鼠越过GSK-3βFL/FL小鼠，以确定是否抑制SMAD-3 β-catenin轴足以消除GSK-3βKO小鼠中的心肌纤维化。目标3：确定 整联蛋白α1β1（ITGα1β1）与纤维化SMAD-3和p38途径的机制以及 确定这种相互作用在调节心肌纤维化调节中的作用。我们的初步数据表明 即使在没有TGF-β1处理的情况下，机械拉伸夫妻即使在没有TGF-β1的情况下激活。主要的 在CFS中表达的整合蛋白是ITGα1β1。在此目标中，我们将检验ITGα1β1负面的假设 调节TGF-β1/SMAD-3和p38途径，从而在心肌纤维化上施加临界突破 重塑。提出的方法是创新的，因为它通过使用新颖的CF-脱离现状。 功能小鼠模型和与之分离的细胞的特定损失，以了解分子机制 心肌纤维化中的心脏纤维化。因此，预计新的研究视野将因此可以实现。 拟议的研究非常重要，因为它提出了防止纤维化重塑的新型策略 患病的心。