MECHANISMS OF DILATED CARDIOMYOPATHY IN CREB A133

扩张型心肌病（DC）是导致 心血管疾病发病率和死亡率， 在这个国家的医疗资源。尽管最近的进展， DC的治疗，这种疾病预后差，5年 死亡率为20 - 50%。在了解 DC的病理生理学和设计这种疾病的新疗法 由于我们对分子生物学的了解相对不足， 疾病的病理生理学和缺乏小动物模型 这与解剖学、生理学和临床上的 人类疾病的特征。 我们最近发现转基因 表达CREB转录的显性阴性形式的小鼠 在心脏特异性α-MHC的控制下的因子（CREBA133） 启动子可重复地产生DC，其类似于许多解剖学上， 人DC的生理和临床特征。 研究中 在这3个协作R01应用程序中，我们建议使用 这种新的小鼠模型，以更好地了解分子途径， CREB调节心肌细胞的稳态， 在这些途径中产生DC。 具体来说，我们将1）阐明 CREB依赖性信号通路是维持心脏 肌细胞稳态，并确定这些途径是如何被扰乱， CREBA 133小鼠与DC，2）确定细胞凋亡的作用， CREBA133 DC和测试的假设，心肌病表型 可以通过心脏中抗凋亡基因的表达来改善， 3)研究兴奋-收缩偶联、收缩力和钙离子 在CREBA 133心肌细胞内稳态，4）了解 心肌细胞功能障碍的肌原纤维和SR缺陷 CREBA 133小鼠，5）研究心室重构和LV-动脉 CREBA 133小鼠中DC发育过程中的偶联，以及6） 确定运动条件反射，性别和不同的影响， 抑制肾素-血管紧张素系统对DC进展的方式 在CREBA133小鼠中。 这些研究代表了 分子生物学家（莱顿）、细胞 生理学家（Moss）小鼠和人类生理学家（Lang，Spencer）， 临床心脏病学家（莱顿，朗，斯宾塞）的大学 芝加哥和威斯康星州。 这项工作的结果应 为我们提供了重要的分子机制的新见解 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.