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

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(申请人提供)：FGF2和TGFbeta1在心脏中的作用 肥大。心肌肥厚被认为是一种适应性反应 心脏受到多重压力，如机械负荷、高血压、 内分泌失衡和肌瘤蛋白突变，最初 增加心输出量，但最终会导致心力衰竭。增加了 心肌细胞大小，肌节蛋白的合成和组织， 胎儿心脏基因表达增加，并诱导即刻早期 基因都是心肌肥大的特征。许多外在因素 如血管活性多肽、IL6家族细胞因子、肾上腺素能激动剂和 机械拉伸已被证明能刺激心肌肥大。最近， 我们已经证明了两个缺乏成纤维细胞生长的小鼠品系 因子-2(FGF2)和转化生长因子β-1(Tgfb1)基因没有 对压力超负荷或降压剂剂量的肥大刺激作出反应 血管紧张素II，分别证明这两种生长因子发挥作用 在心肌肥厚中的重要作用。令人惊讶的是，无论是没有 生长因子或无肥厚必然与 胎儿心脏基因表达增加，这被认为是一种 以心肌肥大为特征的。对信令的理解 这两种生长因子介导心肌肥厚的途径可能是 对于围绕特定信号设计治疗方案非常有用 分子或途径。但由于这两个增长因素都可以通过 多种途径，其中许多途径，如MAP激酶和钙调神经磷酸酶途径， 已经牵涉到心肌肥厚的人，首先要 确定这两种生长因子利用哪条途径(S) 不同的刺激。为此，我们建议施加压力过载和 血管紧张素II对FGF2和Tgfb1基因敲除小鼠的治疗作用 在存在和不存在的情况下激活的差异信号通路 每一种生长因子。对于每一种生长因子，相关的途径 肥大，压力超负荷，肾素血管紧张素系统激活，或 胎儿心脏基因的上调将被评估。