Roles of FGF2 and TGFbeta in cardiac hypertrophy

描述（申请人提供）：FGF 2和TGF β 1在心脏中的作用 肥厚心脏肥大被认为是一种适应性反应， 对心脏的多重压力，如机械负荷，高血压， 内分泌失调和肌节蛋白突变， 增加心输出量，但最终导致心力衰竭。增加 心肌细胞大小，肌节蛋白的合成和组织， 增加胎儿心脏基因的表达，并诱导立即早期 基因都是心脏肥大的特征。许多外在因素 例如血管活性肽、IL 6家族细胞因子、肾上腺素能激动剂和 机械牵拉已经显示出刺激心脏肥大。最近， 我们已经证明，两种成纤维细胞生长缺陷的小鼠品系， 因子-2（Fgf 2）和转化生长因子β-1（Tgfb 1）基因 对压力超负荷或降压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， 在心脏肥大中发挥重要作用。令人惊讶的是， 生长因子也不存在肥大必然与 胎儿心脏基因的表达增加，这被认为是一个 心脏肥大的特征。对信号的理解 这两种生长因子介导心脏肥大的途径可能是 对于围绕特定信号设计治疗方案非常有用 分子或途径。但由于这两种生长因子都可以通过 多种途径，其中许多，如MAP激酶和钙调神经磷酸酶途径， 与心脏肥大有关，首先需要 确定这两种生长因子在以下条件下利用哪种途径 不同的刺激为此，我们建议应用压力过载， 血管紧张素II治疗Fgf 2和Tgfb 1敲除小鼠，然后分析 在存在和不存在的情况下激活的差异信号通路 每一个成长因子对于每种生长因子， 肥大、压力超负荷、肾素血管紧张素系统激活，或 评估胎儿心脏基因的上调。

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.