MECHANISMS OF DILATED CARDIOMYOPATHY IN CREB A133

扩张型心肌病(DC)是 心血管发病率和死亡率，并消耗不成比例的 在这个国家的医疗资源的共享。尽管最近在 DC的治疗，这种疾病的预后很差，5年 死亡率为20%-50%。在理解的进展 树突状细胞的病理生理学及其新的治疗方法 一直受到我们对分子相对缺乏了解的限制 疾病的病理生理学和缺乏小动物模型 它与解剖学、生理学和临床上的 人类疾病的特征。我们最近证明了转基因 表达显性-阴性CREB转录形式的小鼠 心脏特异性α-MHC控制下的因子(CREBA133) 启动子可复制地产生DC，类似于许多解剖上的， 人树突状细胞的生理和临床特征。在研究中 在我们建议使用的这3个协作R01应用程序中进行了描述 这一新的小鼠模型通过以下方式更好地理解分子途径 哪些CREB调节心肌细胞的动态平衡以及如何扰动 在这些途径中产生DC。具体地说，我们将1)阐明 维持心脏功能所需的CREB依赖的信号通路 并确定这些通路是如何被扰乱的 CREBA133小鼠DC，2)确定细胞凋亡在DC中的作用 CREBAl33 DC，并检验心肌病表型的假设 可以通过在心脏中表达抗凋亡基因来改善， 3)研究兴奋收缩偶联、收缩能力和钙离子 CREBA133心肌细胞的归巢，4)了解 肌原纤维和肌浆网缺陷导致心肌细胞功能障碍 CREBA133小鼠，5)研究心室重构和左动脉 CREBA133小鼠DC发育过程中的偶联，以及6) 确定锻炼条件、性别和不同因素的影响 抑制肾素血管紧张素系统在DC进展中的作用 在CREBA133小鼠身上。这些研究代表了一种 分子生物学家(莱顿)、细胞之间建立了合作 生理学家(Moss)老鼠和人类生理学家(Lang，Spencer)和 临床心脏病专家(莱顿、朗、斯宾塞) 芝加哥和威斯康星州。总而言之，这项工作的结果应该是 为我们提供了对分子机制的重要新见解 潜在的人类DC和CHF。

Dilated cardiomyopathy (DC) represents an important cause of cardiovascular morbidity and mortality and consumes a disproportionate share of medical resources in this country. Despite recent advances in the treatment of DC, this disorder has a poor prognosis with 5 year mortality rates of 20-50 percent. Progress in understanding the pathophysiology of DC and in devising new therapies for this disorder has been limited by our relative lack of understanding of the molecular pathophysiology of the disease and by the lack of a small animal model which closely resembles the anatomical, physiological, and clinical features of the human disease. We have recently shown that transgenic mice expressing a dominant-negative form of the CREB transcription factor (CREBA133) under the control of the cardiac-specific alpha-MHC promoter reproducibly develop DC that resembles many of the anatomical, physiological and clinical features of human DC. In the studies described in these 3 collaborative R01 applications we propose to use this new mouse model to better understand the molecular pathways by which CREB regulates cardiac myocyte homeostasis and how perturbations in these pathways produce DC. Specifically we will 1) elucidate the CREB-dependent signaling pathways that are required to maintain cardiac myocyte homeostasis and determine how these pathways are perturbed in the CREBA133 mice with DC, 2) determine the role of apoptosis in the CREBAl33 DC and test the hypothesis that the cardiomyopathic phenotype can be ameliorated by expression of anti-apoptotic genes in the heart, 3) study excitation-contraction coupling, contractility, and calcium homestasis in the CREBA133 cardiac myocytes, 4) understand the myofibrillar and SR defects underlying cardiac myocyte dysfunction in the CREBA133 mice, 5) study ventricular remodeling and LV-arterial coupling during the development of DC in the CREBA133 mice, and 6) determine the effects of exercise conditioning, gender, and different modes of inhibiting the renin angiotensin system on progression of DC in the CREBA133 mice. These studies represent the continuation of an established collaboration between molecular biologists (Leiden), cell physiologists (Moss) mouse and human physiologists (Lang, Spencer) and clinical cardiologists (Leiden, Lang, Spencer) the Universities of Chicago and Wisconsin. Taken together the results of this work should provide us with important new insights into the molecular mechanisms underlying human DC and CHF.