Roles of FGF2 and TGFbeta in cardiac hypertrophy

FGF2 和 TGFbeta 在心脏肥大中的作用

• 批准号: 6729931
• 负责人: THOMAS DOETSCHMAN
• 金额: $ 37.91万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729931
• 关键词: angiotensin II; biological signal transduction; fibroblast growth factor; functional /structural genomics; gene expression; gene targeting; genetic regulation; genetically modified animals; in situ hybridization; intracardiac pressure; laboratory mouse; mitogen activated protein kinase; physiologic stressor; protein isoforms; protein kinase C; protein localization; transforming growth factors; ventricular hypertrophy; angiotensin II; biological signal transduction; fibroblast growth factor; functional /structural genomics; gene expression; gene targeting; genetic regulation; genetically modified animals; in situ hybridization; intracardiac pressure; laboratory mouse; mitogen activated protein kinase; physiologic stressor; protein isoforms; protein kinase C; protein localization; transforming growth factors; ventricular hypertrophy

DESCRIPTION (provided by applicant): Roles of FGF2 and TGFbeta1 in cardiac hypertrophy. Cardiac hypertrophy is thought to be an adaptive response to multiple stresses on the heart, such as mechanical load, hypertension, endocrine imbalance and mutations in sarcomeric proteins, which initially increase cardiac output, but eventually lead to heart failure. Increased cardiomyocyte size, synthesis and organization of sarcomeric proteins, increased expression of fetal cardiac genes, and induction of immediate-early genes are all characteristics of cardiac hypertrophy. Many extrinsic factors such as vasoactive peptides, IL6 family cytokines, adrenergic agonists and mechanical stretch have been shown to stimulate cardiac hypertrophy. Recently, we have shown that two mouse strains deficient for the Fibroblast Growth Factor-2 (Fgf2) and Transforming Growth Factor beta-1 (Tgfb1) genes do not respond to the hypertrophic stimuli of pressure overload or subpressor doses of angiotensin II, respectively, demonstrating that these two growth factors play essential roles in cardiac hypertrophy. Surprisingly, neither the absence of growth factor nor the absence of hypertrophy necessarily correlated with increased expression of fetal cardiac genes, which is thought to be a characteristic of cardiac hypertrophy. An understanding of the signaling pathways by which these two growth factors mediate cardiac hypertrophy would be quite useful for designing therapeutic protocols around specific signaling molecules or pathways. But since both growth factors can signal through multiple pathways, many of which, such as MAP kinase and calcineurin pathways, have been implicated in cardiac hypertrophy, it will first be necessary to determine which pathway(s) are utilized by these two growth factors under different stimuli. To this end we propose to apply pressure overload and angiotensin II treatment to both Fgf2 and Tgfb1 knockout mice and then analyze the differential signaling pathways activated in the presence and absence of each growth factor. For each growth factor the pathways that correlate with hypertrophy, pressure overload, activation of the renin angiotensin system, or upregulation of fetal cardiac genes will be assessed.

描述（由申请人提供）：FGF2和TGFBETA1在心脏中的作用 肥大。心脏肥大被认为是对 心脏上的多种压力，例如机械负荷，高血压， 肉瘤蛋白中的内分泌失衡和突变，最初 增加心输出量，但最终导致心力衰竭。增加 心肌细胞的大小，合成和肌肉蛋白的组织， 胎儿心脏基因的表达增加，并立即诱导 基因都是心脏肥大的特征。许多外部因素 例如血管活性肽，IL6家族细胞因子，肾上腺素能激动剂和 机械拉伸已显示可刺激心脏肥大。最近， 我们已经表明，两种小鼠菌株不足以成纤维细胞生长 因子-2（FGF2）和转化生长因子β-1（TGFB1）基因不得 应对压力超负荷或亚压剂量的肥厚刺激 血管紧张素II分别表明这两个生长因子发挥了 心脏肥大的基本作用。令人惊讶的是，没有 生长因子也不存在肥大一定与 胎儿心脏基因的表达增加，这被认为是 心脏肥大的特征。对信号的理解 这两个生长因子介导心脏肥大的途径是 对于设计特定信号的治疗方案非常有用 分子或途径。但是由于两个增长因素都可以通过 多个途径，其中许多途径，例如MAP激酶和钙调神经酶途径， 已经与心脏肥大有关，首先需要 确定这两个增长因素在 不同的刺激。为此，我们建议施加压力超负荷和 血管紧张素II治疗FGF2和TGFB1敲除小鼠，然后分析 在存在和不存在的情况下激活的差分信号通路 每个生长因子。对于每个增长因素，与 肥大，压力超负荷，肾素血管紧张素系统的激活或 将评估胎儿心脏基因的上调。