Signaling in pathological & physiological hypertrophy

描述：（由申请人提供）：响应于各种各样的刺激， 心脏具有进行肥大生长的能力。肥大可能是 在发育过程中或对运动的反应中的生理适应过程。它 在病理性刺激如压力超负荷之后最初是适应性的 但会变得适应不良，事实上， 心衰导致肥大的调节反馈系统包括 多种细胞内因子和信号级联。因为多 在这些条件下激活的因子和信号通路是共同的， 这两种刺激，关键是要了解哪些共同和独特的途径， 导致病理性与生理性肥大。我们将使用几个 转基因模型，以帮助描绘参与的信号转导过程， 病理性和生理性肥大的进展。心脏表型 缺乏肥大细胞内信使（MEKKI）的转基因系 信号级联将表征其对病理和 生理性肥大刺激。此外，这只老鼠将被杂交到 三种肥厚型心肌病的转基因模型 (HCM)，其在心脏肌节蛋白中具有特定突变。之一 这些转基因模型在肌动蛋白结合结构域中具有突变， 鼠α-肌球蛋白重链（α-MHC），其特征在于性别特异性 心室质量增加。另外的模型含有错义突变， 心肌肌钙蛋白T（cTnT）或截短的cTnT。有趣的是，cTnT突变 导致心室质量显著降低。这些杂交的动物将 分析以确定MEKK 1的整合和贡献 细胞内途径的HCM的不同表型。

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.