CONGESTIVE HEART FAILURE IN TNF ALPHA TRANSGENIC MICE

描述：特发性扩张性心力衰竭 心肌病（CHF）是一种在美国流行的疾病。 在美国有400万人被诊断为CHF， 这些患者的病因尚不清楚。 患者 心力衰竭具有疲劳、呼吸短促和水肿症状， 5年死亡率80%。 不幸的是，尽管二十多年来， 临床和研究调查，我们改善症状的能力， 幸存者令人失望。 1991年，人们首次认识到， CHF患者血清中促炎因子水平升高， 细胞因子肿瘤坏死因子α（TNF α）。 随后的研究 证明：1）失败的，而不是非失败的人类心脏 表达大量的TNF α; 2）TNF α是一种有效的阴性表达， 正性肌力药;和3）TNF α水平与心脏收缩力之间的反比关系。 血流动力学 然而，这些研究并没有确定TNF α是否 表达是与充血性心力衰竭相关的附带现象， 病理生理意义 此外，临床治疗策略 不存在靶向细胞因子表达。 最近，PI 开发了一种转基因小鼠，在心脏中过度表达TNF α， 具体方式。 初步评估表明，这些转基因 小鼠在6个月大时发展出与 扩张型心肌病：1）心室扩张; 2）心房扩张： 3)间质纤维化; 4）轻度间质浸润; 5）减少 射血分数; 6）肾上腺素能反应性减弱;以及7） 心源性猝死 因此，他假设这些小鼠将提供一种 一种新的模型，其中评估TNF α在发展中的作用， 晚期扩张型心肌病 这项建议包括两个具体目标： 具体目标1将检验TNF α在肿瘤细胞中过表达的假设。 小鼠影响l）形态学和组织学; 2）生化和分子生物学 生物学，3）功能性;和4）电生理学变化， 与扩张型心肌病的表现一致 使用新颖 为老鼠设计或修改的技术，他将评估这些 在扩张和失败的发展过程中的各种参数。 在 具体目标2他将测试的假设，发展的末期 失败可以通过调节上游的信号通路来减弱， TNF α受体激活的下游。 方法包括：1） 用单克隆TNF α抗体治疗，2）腺病毒介导的基因 可溶性TNF α受体的转移，和3）异交TNF α 过表达小鼠与具有增强的肾上腺素能活性的转基因小鼠 由于BARK抑制剂或β 2肾上腺素能受体的过度表达 受体的 这些研究应加强我们对 促炎细胞因子在CHF中的作用，验证了这种独特的 模型，并提供宝贵的信息，设计模式治疗 CHF患者的治疗策略。

DESCRIPTION: Congestive heart failure due to idiopathic dilated cardiomyopathy (CHF) is a disease of epidemic proportions in the U.S. Nearly 4 million people in the U.S. have the diagnosis of CHF and in nearly half of these patients the etiology of their disease is unknown. Patients with heart failure have symptoms of fatigue, shortness of breath and edema and a 5 year mortality of 80%. Unfortunately, despite over two decades of both clinical and research investigations, our ability to improve symptoms and alter survival is disappointing. In 1991, it was first recognized that patients with CHF have elevated serum levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). Subsequent studies have demonstrated: 1) that the failing but not the non-failing human heart expresses robust amounts of TNFalpha; 2) that TNFalpha is a potent negative inotrope; and 3) an inverse relationship between TNFalpha levels and cardiac hemodynamics. However, these studies did not define whether TNFalpha expression was an epiphenomenon associated with congestive failure or of pathophysiologic significance. Furthermore, clinical therapeutic strategies targeted at cytokine expression do not exist. Recently, the PI has developed a line of transgenic mice that over-express TNFalpha in a cardiac specific manner. Preliminary evaluations demonstrate that these transgenic mice develop a phenotype at 6 months of age that is consistent with that of dilated cardiomyopathy: 1) ventricular dilatation; 2) atrial dilatation: 3) interstitial fibrosis; 4) mild interstitial infiltrates; 5) a diminished ejection fraction; 6) attenuation of adrenergic responsiveness; and 7) sudden cardiac death. Thus, he hypothesizes that these mice will provide a novel model in which to evaluate the role of TNFalpha in the development of end-stage dilated cardiomyopathy. This proposal includes two specific aims: Specific Aim 1 will test the hypothesis that TNFalpha over-expression in the mouse effects l) morphologic and histologic; 2) biochemical and molecular biological, 3) functional; and 4) electrophysiologic changes that are consistent with those seen in dilated cardiomyopathy. Using novel technology designed for or modified to the mouse, he will assess these various parameters during the development of dilatation and failure. In Specific Aim 2 he will test the hypothesis that the development of end-stage failure can be attenuated by modulating signaling pathways upstream or downstream of TNFalpha receptor activation. Approaches will include: 1) therapy with monoclonal TNFalpha antibody, 2) adenoviral mediated gene transfer of soluble TNFalpha receptors, and 3) out-crossing TNFalpha overexpression mice with transgenic mice having enhanced adrenergic activity due to over- expression of BARK inhibitor or of the beta2 adrenergic receptor. These studies should enhance our understanding of the role of pro- inflammatory cytokines in CHF, validate the usefulness of this unique model, and provide invaluable information for designing mode therapeutic strategies in patients with CHF.