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-超家族成员在调节肥厚，炎症和 失败和重塑的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。通过刺激一系列细胞内效应，TGF-S的作用 接收器激活的SMADS（R-SMADS）或通过独立于SMAD的途径。内源性负 TGF-信号传导级联的调节器可能在心脏重塑中起重要的保护作用， 限制纤维化或肥大反应。抑制性smads（i-smads），smad6和smad7 在许多细胞类型的TGF-反应的负面调节中已隐含。 当前的建议使用新生成的细胞特异性敲除小鼠进行调查 首次在调节心脏重塑中的I-SMADS，SMAD6和SMAD7的作用 压力过多的心脏。我们的初步数据表明在 心肌细胞，成纤维细胞和巨噬细胞，但在淋巴细胞和嗜中性粒细胞中不渗透 压力过多的心肌，并提出心肌细胞和成纤维细胞特异性的关键作用 SMAD7在保护心脏免受不良重塑和功能障碍的影响方面。细胞的作用 I-SMADS的具体作用和由Smad6和Smad7调制的分子信号将 在3个特定目标中进行探讨： 特定目的1：探索SMAD7在调节心肌细胞中的作用 和巨噬细胞表型在压力过多的心脏中。我们的初步研究表明 心脏压力超负荷后，SMAD7明显上调，并位于 心肌细胞，活化的肌纤维细胞和巨噬细胞，但在淋巴细胞和中性粒细胞中没有。 彼此之间，我们将研究SMAD7调节的细胞特异性机制，我们将使用 心肌细胞，成纤维细胞/肌纤维细胞和髓样细胞特异性SMAD7敲除小鼠 由我们的实验室生成，以探索SMAD7在压力越过的人中的细胞效应 心肌。 特定目的2：剖析负责影响的分子机制 Smad7体内和体外。 SMAD7的动作可能涉及调节R-SMAD依赖性途径， 对独立于SMAD的信号级联反应或与TGF-非依赖性信号的相互作用的影响。这 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，以及涉及纤维，炎性和肥厚的调节的旁分泌信号 响应将在体外和体内研究，使用功能障碍方法。 特定目的3：研究SMAD6在压力重塑的重塑中的作用 心肌。我们的初步研究表明，压力越过的smad6诱导 心肌和心肌细胞，成纤维细胞和巨噬细胞的定位。有条件的Smad6 敲除小鼠将用于剖析SMAD6的细胞特异性作用 心脏和负责SMAD6介导的作用的机制将在体内和体外探索。 该提案首次调查了Smad6和Smad7在心脏重塑中的作用， 解剖其分子靶标和作用机制。提议的意义 实验超出了心血管领域，为生物学提供了新的见解 TGF-超家族。