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

基本信息

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
项目类别：
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

项目摘要

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 超家族成员在肥厚、炎症和代谢性疾病的调节中发挥着核心作用。衰竭和重塑心脏的纤维化反应，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器发挥作用。受体激活的 Smads (R-Smads)，或通过内源性负性途径。 TGF-β信号级联的调节因子可能在心脏重塑中发挥重要的保护作用，通过抑制纤维化或肥大反应。抑制性 Smads (I-Smads)、Smad6 和 Smad7。与许多细胞类型中 TGF-β 反应的负调节有关。目前的提案使用新生成的细胞特异性敲除小鼠来研究首次研究了 I-Smads、Smad6 和 Smad7 在调节心脏重构中的作用我们的初步数据表明 Smad6 和 Smad7 在心脏中的诱导作用。心肌细胞、成纤维细胞和巨噬细胞，但不存在于浸润的淋巴细胞和中性粒细胞中压力超负荷的心肌，并表明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细胞功能障碍方面的作用。 I-Smads 的具体作用以及 Smad6 和 Smad7 调节的分子信号将探索 3 个具体目标：具体目标1：探讨Smad7对心肌细胞、成纤维细胞的调节作用我们的初步研究表明，压力超负荷的心脏中的巨噬细胞表型。 Smad7 在心脏压力超负荷后显着上调，并且定位于心肌细胞、活化的肌成纤维细胞和巨噬细胞，但淋巴细胞和中性粒细胞中没有。因此，我们将研究 Smad7 调节的细胞特异性机制，并且我们将使用最近，心肌细胞、成纤维细胞/肌成纤维细胞和骨髓细胞特异性 Smad7 敲除小鼠由我们实验室生成，旨在探索 Smad7 在压力超载时的细胞效应心肌。具体目标2：剖析造成影响的分子机制 Smad7 在体内和体外的作用可能涉及 R-Smad 依赖性途径的调节，对 Smad 独立信号级联的影响，或与 TGF-β 独立信号的相互作用。 Smad7 依赖性心肌细胞、成纤维细胞和巨噬细胞调节的分子机制表型以及参与纤维形成、炎症和肥厚调节的旁分泌信号将使用功能丧失和获得的方法在体外和体内研究。具体目标3：研究Smad6在压力过载重塑中的作用我们的初步研究表明 Smad6 在压力超负荷时会被诱导。心肌细胞、成纤维细胞和巨噬细胞中的定位。敲除小鼠将用于剖析 Smad6 在压力超载时的细胞特异性作用心脏，以及 Smad6 介导作用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，剖析其分子靶点和作用机制的意义。实验超出了心血管领域，为心血管生物学提供了新的见解 TGF-β超家族。