Regulation of the TGF-beta superfamily in the remodeling and failing heart

TGF-β超家族在心脏重塑和衰竭中的调节

• 批准号: 10591491
• 负责人: Nikolaos G Frangogiannis
• 金额: $ 54.99万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591491
• 关键词: Adult; Biological; Biology; Blood Vessels; Bone Morphogenetic Proteins; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiovascular system; Cell Nucleus; Cells; Complex; Data; Development; Disease; EFRAC; Embryonic Development; Experimental Models; Feedback; Fibroblasts; Fibrosis; Follistatin; Functional disorder; Genetic Transcription; Heart; Heart failure; Human; Hypertension; Hypertrophy; Immune; In Vitro; Inflammatory; Knockout Mice; Laboratories; Left; Left Ventricular Outflow Obstruction; Lymphocyte; Lymphocytic Infiltrate; MAP Kinase Gene; Macrophage; Mediating; Molecular; Molecular Target; Myeloid Cells; Myocardial; Myocardium; Myofibroblast; Neutrophil Infiltration; Paracrine Communication; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Physiologic intraventricular pressure; Play; Regulation; Research Personnel; Role; Series; Signal Transduction; Thick; Time; Transforming Growth Factor beta; Transforming Growth Factors; Ventricular; Ventricular Dysfunction; cell type; experimental study; gain of function; heart preservation; in vivo; inhibitor; injured; insight; interstitial cell; loss of function; member; neutrophil; p38 Mitogen Activated Protein Kinase; preservation; pressure; prevent; receptor; response; restraint

TGF- superfamily members play a central role in regulation of hypertrophic, inflammatory, and fibrotic responses in failing and remodeling hearts, modulating phenotype and function of both cardiomyocytes and interstitial cells. TGF-s act by stimulating a series of intracellular effectors the receptor-activated Smads (R-Smads), or through Smad-independent pathways. Endogenous negative regulators of TGF- signaling cascades may play an important protective role in cardiac remodeling, by restraining fibrotic or hypertrophic responses. The inhibitory Smads (I-Smads), Smad6 and Smad7 have been implicated in negative regulation of TGF- responses in many cell types. The current proposal uses newly-generated cell-specific knockout mice to investigate for the first time the role of the I-Smads, Smad6 and Smad7 in regulation of cardiac remodeling in the pressure-overloaded heart. Our preliminary data demonstrate induction of Smad6 and Smad7 in cardiomyocytes, fibroblasts and macrophages, but not in lymphocytes and neutrophils infiltrating the pressure-overloaded myocardium, and suggest critical roles of cardiomyocyte and fibroblast-specific Smad7 in protection of the heart from adverse remodeling and dysfunction. The role of the cell- specific actions of the I-Smads and the molecular signals modulated by Smad6 and Smad7 will be explored in 3 specific aims: Specific aim 1: to explore the role of Smad7 in regulation of cardiomyocyte, fibroblast and macrophage phenotype in the pressure-overloaded heart. Our preliminary studies show that Smad7 is markedly upregulated following cardiac pressure overload, and is localized in cardiomyocytes, activated myofibroblasts, and macrophages, but not in lymphocytes and neutrophils. Accordingly, we will study cell-specific mechanisms of Smad7 regulation, and we will use cardiomyocyte, fibroblast/myofibroblast, and myeloid cell-specific Smad7 knockout mice, recently generated by our laboratory, to explore the cellular effects of Smad7 in the pressure-overloaded myocardium. Specific aim 2: to dissect the molecular mechanisms responsible for the effects of Smad7 in vivo and in vitro. Smad7 actions may involve modulation of R-Smad-dependent pathways, effects on Smad-independent signaling cascades, or interactions with TGF--independent signals. The molecular mechanisms for Smad7-dependent regulation of cardiomyocyte, fibroblast and macrophage phenotype, and the paracrine signals involved in regulation of fibrogenic, inflammatory and hypertrophic responses, will be studied in vitro and in vivo, using both loss and gain-of-function approaches. Specific aim 3: to investigate the role of Smad6 in remodeling of the pressure-overloaded myocardium. Our preliminary studies show induction of Smad6 in the pressure-overloaded myocardium, and localization in cardiomyocytes, fibroblasts and macrophages. Conditional Smad6 knockout mice will be used to dissect the cell-specific actions of Smad6 in the pressure-overloaded heart, and the mechanisms responsible for Smad6-mediated effects will be explored in vivo and in vitro. The proposal investigates for the first time the role of Smad6 and Smad7 in cardiac remodeling, dissecting their molecular targets and mechanisms of action. The significance of the proposed experiments extends beyond the cardiovascular field, providing new insights into the biology of the TGF- superfamily.

转化生长因子-超家族成员在肥大、炎性和 衰竭和重塑心脏的纤维化反应，对两者的表型和功能的调节 心肌细胞和间质细胞。转化生长因子-S通过刺激一系列细胞内效应器发挥作用 受体激活的Smads(R-Smads)，或通过Smad不依赖的途径。内源性负性 转化生长因子-信号通路的调节可能通过以下途径在心脏重构中发挥重要的保护作用 抑制纤维化或肥大反应。抑制性SMADS(I-SMADS)、Smad6和Smad7 在许多细胞类型中都与转化生长因子-反应的负调控有关。 目前的方案使用新产生的细胞特异性基因敲除小鼠来研究 首次研究I-Smads、Smad6和Smad7在心脏重构调节中的作用 压力超负荷的心脏。我们的初步数据显示Smad6和Smad7在 心肌细胞、成纤维细胞和巨噬细胞，但不存在于淋巴细胞和中性粒细胞中。 压力超负荷的心肌，提示心肌细胞和成纤维细胞的关键作用 Smad7在保护心脏免受不良重塑和功能障碍的影响。细胞的作用-- I-SMADs的特定作用以及Smad6和Smad7调制的分子信号将 在三个具体目标中进行探索： 特异性目的1：探讨Smad7在心肌细胞、成纤维细胞调节中的作用 和压力超负荷心脏的巨噬细胞表型。我们的初步研究表明 Smad7在心脏压力超负荷后显著上调，并定位于 心肌细胞、活化的肌成纤维细胞和巨噬细胞，但不存在于淋巴细胞和中性粒细胞。 因此，我们将研究Smad7调控的细胞特异性机制，并将使用 心肌细胞、成纤维细胞/肌成纤维细胞和髓系细胞特异性Smad7基因敲除小鼠 本实验室制作，以探讨Smad7在压力超负荷中的细胞效应 心肌。 具体目标2：剖析导致这些效应的分子机制。 Smad7在体内和体外的表达。Smad7的作用可能涉及调节R-Smad依赖的通路， 对Smad非依赖性信号通路的影响，或与转化生长因子-非依赖性信号的相互作用。这个 Smad7依赖的心肌细胞、成纤维细胞和巨噬细胞调控的分子机制 表型和旁分泌信号参与调节纤维化、炎症和肥大 反应，将在体外和体内进行研究，使用功能丧失和功能获得的方法。 具体目标3：探讨Smad6在压力超负荷心肌重塑中的作用 心肌。我们的初步研究表明，在压力超负荷的情况下Smad6的诱导 心肌，以及心肌细胞、成纤维细胞和巨噬细胞的定位。有条件的Smad6 基因敲除小鼠将被用来分析Smad6在压力超负荷中的细胞特异性行为 Smad6介导的效应的机制将在体内和体外进行探索。 该提案首次研究了Smad6和Smad7在心脏重构中的作用， 剖析它们的分子靶点和作用机制。建议的重要意义 实验超越了心血管领域，为心血管疾病的生物学提供了新的见解 转化生长因子-超家族。