Signaling in pathological & physiological hypertrophy

描述：(申请人提供)：响应各种各样的刺激， 心脏有能力经历肥大的生长。肥大可能是一种 生理适应在发育过程中或对运动的反应中的生理适应过程它 在受到病理性刺激(如压力过载)后最初是适应的 但可能会变得不适应，实际上是充血的主要预测因素 心力衰竭。导致肥大的调节反馈系统包括 各种细胞内因子和信号级联反应。因为这个倍数 在这些条件下激活的因子和信号通路是常见的 这两种刺激，关键是要了解哪些共同和不同的途径 导致病理性肥大与生理性肥大。我们将使用几个 转基因模型，以帮助描绘信号过程中涉及的 病理性和生理性肥大的进展。中国人的心脏表型 缺乏肥大细胞内信使(Mekki)的转基因株系 信号级联反应的特点是其对病理和 生理性肥大刺激。此外，此鼠标将被交叉到 肥厚型心肌病的三个转基因模型 (HCM)，它在心脏肌瘤蛋白中含有特定的突变。其中之一 这些转基因模型的肌动蛋白结合域发生了突变 小鼠α-肌球蛋白重链(a-MHC)，其特征是具有性别特异性 脑室重量增加。其他模型包含错义突变 心肌肌钙蛋白T(CTnT)或截短型cTnT。有趣的是，cTnT突变 结果显著降低了心室质量。这些杂交的动物会 被分析以确定MEKK1的整合和贡献 不同表型HCM的细胞内途径。

DESCRIPTION: (provided by applicant): In response to a wide variety of stimuli, the heart has the ability to undergo hypertrophic growth. Hypertrophy can be a physiologic adaptive process during development or in response to exercise. It is initially adaptive after a pathological stimulus such as pressure overload but can become maladaptive and is, in fact, a leading predictor of congestive heart failure. The regulatory feedback systems leading to hypertrophy include a variety of intracellular factors and signaling cascades. Because the multiple factors and signaling pathways activated under these conditions are common to both stimuli, it is critical to understand which common and distinct pathways lead to pathologic versus physiological hypertrophy. We will use several transgenic models to help delineate the signaling processes involved in the progression of pathologic and physiologic hypertrophy. The cardiac phenotype of a transgenic line lacking an intracellular messenger (MEKKI) of a hypertrophic signaling cascade will be characterized for its response to pathologic and physiologic hypertrophic stimuli. In addition, this mouse will be crossed to three, well-characterized transgenic models for hypertrophic cardiomyopathy (HCM), which harbor specific mutations in cardiac sarcomeric proteins. One of these transgenic models has a mutation in the actin-binding domain of the murine a-myosin heavy chain (a-MHC) and is characterized by a gender specific increased ventricular mass. Additional models contain a missense mutation of cardiac troponin T (cTnT) or a truncated cTnT. Interestingly, cTnT mutations result in significantly decreased ventricular mass. These crossed animals will be analyzed to determine the integration and contribution of the MEKK1 intracellular pathway to the varied Phenotypes of HCM.