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: 10360502
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360502
• 关键词: Adult; Biological; Biology; Blood Vessels; Bone Morphogenetic Proteins; Cardiac; Cardiac Myocytes; Cardiovascular system; Cell Nucleus; Cells; Complex; Data; Disease; EFRAC; Embryonic Development; Experimental Models; Feedback; Fibroblasts; Fibrosis; Follistatin; Functional disorder; Genes; Growth Factor Receptors; Heart; Heart failure; Human; Hypertension; Hypertrophy; Immune; In Vitro; Inflammatory; Knockout Mice; Laboratories; Lead; Left; Left Ventricular Outflow Obstruction; Lymphocyte; Lymphocytic Infiltrate; MAP Kinase Gene; Mediating; Molecular; Molecular Target; Myeloid Cells; Myocardial; Myocardium; Myofibroblast; Neutrophilic Infiltrate; 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; cardiogenesis; cell type; experimental study; gain of function; heart preservation; in vivo; inhibitor; injured; insight; interstitial cell; macrophage; member; neutrophil; p38 Mitogen Activated Protein Kinase; preservation; pressure; prevent; receptor; response

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.

TGF-β 1超家族成员在调节肥大性、炎症性和巨噬细胞增殖中起重要作用。 衰竭和重塑心脏中的纤维化反应，调节两者的表型和功能 心肌细胞和间质细胞。TGF-β通过刺激一系列细胞内效应物起作用， 受体激活的Smads（R-Smads），或通过Smad非依赖性途径。内源性阴性 TGF-β信号级联调节因子可能在心脏重塑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 在许多细胞类型中参与TGF-β反应的负调节。 目前的建议使用新产生的细胞特异性敲除小鼠来研究 首次证实了I-Smads、Smad6和Smad7在心肌重塑中的调节作用。 压力超负荷的心脏我们的初步数据表明，Smad6和Smad7的诱导， 心肌细胞，成纤维细胞和巨噬细胞，但不是在淋巴细胞和中性粒细胞浸润 压力超载的心肌，并建议心肌细胞和成纤维细胞特异性 Smad7在保护心脏免受不良重塑和功能障碍中的作用。细胞的作用- I-Smads的特定作用以及Smad 6和Smad 7调节的分子信号将 在3个具体目标中进行探索： 具体目的1：探讨Smad7在心肌细胞、成纤维细胞、成纤维细胞中的调控作用 和巨噬细胞表型。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中，但在淋巴细胞和中性粒细胞中不存在。 因此，我们将研究Smad7调控的细胞特异性机制， 心肌细胞、成纤维细胞/肌成纤维细胞和髓样细胞特异性Smad7敲除小鼠， 我们的实验室产生的，探索Smad7在压力过载的细胞作用， 心肌 具体目标2：剖析造成下列影响的分子机制： Smad7在体内和体外。Smad7的作用可能涉及R-Smad依赖性通路的调节， 对Smad非依赖性信号级联的影响，或与TGF-β非依赖性信号的相互作用。的 Smad7依赖性调节心肌细胞、成纤维细胞和巨噬细胞的分子机制 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，使用功能丧失和获得的方法。 具体目标3：研究Smad6在压力超负荷的重构中的作用。 心肌我们的初步研究表明，Smad6在压力超载的诱导 心肌，以及心肌细胞、成纤维细胞和巨噬细胞中的定位。条件Smad6 敲除小鼠将被用于解剖Smad6在压力过载中的细胞特异性作用。 心脏，负责Smad6介导的影响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在心脏重塑中的作用， 剖析它们的分子靶点和作用机制。建议的意义 实验延伸到心血管领域之外，为心脏病的生物学提供了新的见解。 TGF-β超家族。