CONGESTIVE HEART FAILURE IN TNF ALPHA TRANSGENIC MICE

描述：特发性扩张性充血性心力衰竭 心肌病(CHF)是一种在美国几乎流行的疾病。 美国有400万人被诊断为慢性心力衰竭，近一半的人 这些患者的病因尚不清楚。患有疾病的患者 心力衰竭有疲倦、呼吸急促和浮肿的症状， 5年死亡率为80%。不幸的是，尽管两人都经历了20多年的 临床和研究调查，我们改善症状和 另一种生存方式令人失望。1991年，人们首次认识到 充血性心力衰竭患者血清促炎因子水平升高 细胞因子肿瘤坏死因子α(TNFpha)。随后的研究发现 证明：1)失败而不是不失败的人的心 表达大量的肿瘤坏死因子α；2)表明肿瘤坏死因子α是一个强有力的负面因素 3)肿瘤坏死因子α水平与心脏功能呈负相关。 血流动力学。然而，这些研究并未定义肿瘤坏死因子α是否 表达是一种伴随现象，与充血性衰竭或 病理生理学意义。此外，临床治疗策略 靶向细胞因子的表达不存在。最近，国际刑警组织已经 开发了一种转基因小鼠，在心脏组织中过表达肿瘤坏死因子α 具体的方式。初步评估表明，这些转基因 小鼠在6个月大时形成一种表型，这与 扩张型心肌病：1)心室扩张；2)心房扩张： 3)间质纤维化；4)轻度间质浸润性病变；5)间质纤维化 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，他假设这些老鼠将提供一种 评估肿瘤坏死因子α在肿瘤发生发展中作用的新模型 终末期扩张型心肌病。这项建议包括两个具体目标： 特定目标1将检验以下假设：肿瘤坏死因子α在肿瘤细胞中过度表达 小鼠效应L)形态和组织学；2)生化和分子 生物学，3)功能；以及4)电生理变化， 与扩张型心肌病一致。使用小说 为鼠标设计或修改的技术，他将评估这些 各种参数在发展过程中的膨胀和破坏。在……里面 具体目标2他将检验这一假说，即发展到末期 故障可以通过调节上游信号通路或 在肿瘤坏死因子α受体激活下游。方法包括：1) 单抗治疗，2)腺病毒介导的基因治疗 可溶性肿瘤坏死因子α受体的转移，以及3)异交。 高表达转基因小鼠增强了肾上腺素能活性 由于树皮抑制物或β2肾上腺素能的过度表达 受体。这些研究应该会加深我们对 促炎症细胞因子在CHF中的作用，验证了这一独特的 模型，并为设计治疗模式提供了宝贵的信息 慢性心力衰竭患者的治疗策略。

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.