Protection from Radiation Induced Cardiomyopathy

描述(由申请人提供)：心脏的辐射损伤可能发生在各种恶性肿瘤的放射治疗(XRT)的背景下。而心脏最初的(急性)损伤 由于潜在疾病通常多年内不明显，随着癌症治疗的日益成功，更多既往接受过XRT的患者将拥有正常(或接近正常)的预期寿命，现在可能面临XRT长期并发症的风险。白介素1(IL-1)以两种形式存在，是参与几乎所有炎症反应的典型细胞因子。外源性给予IL-1会导致小鼠左室收缩功能障碍，并损害收缩储备，在急性心肌梗死(AMI)的实验模型中复制心力衰竭的表型。最初的损伤导致存活心肌的丧失，从而促使以进行性心脏增大和功能障碍为特征的非适应性重塑过程(不利重塑)，导致心力衰竭和心源性死亡。IL-1RI基因缺失的小鼠在急性心肌梗死后有明显更有利的心脏重塑(较少扩大和功能障碍)。IL-1β(使用重组人IL-1ra[anakinra]、IL-1Trap和抗IL-1β抗体)的药理和遗传抑制都限制了不利的重塑过程，并提高了存活率。我们认为，用Anakinra阻断IL-1可能是预防、限制或治疗XRT诱导的心肌病的一种策略。这项提议有两个具体目标。第一个是确定IL-1活性增加(早期或晚期) XRT暴露有助于小鼠心肌病的发展，以及IL-1信号的遗传抑制是否可以改善XRT诱导的心肌病的发展。第二个是确定IL-1信号的药物阻断是否影响XRT诱导的小鼠心肌病的发展。我们建议的研究旨在阐明XRT诱导的心肌病发生的基础，具有双重目标：确定预防这种疾病状态发展的治疗策略，以及挽救因以前的放射治疗而导致疾病发展的患者。

DESCRIPTION (provided by applicant): Radiation injury to the heart may occur in the context of radiation therapy (XRT) for various malignancies. While the initial (acute) injury to the heart must, of necessity, occur shortly after XRT, latent disease is generally not evident for many years, With the increasing success of cancer treatments, more patients with prior XRT will have a normal (or near-normal) life expectancy and may now be at risk for long-term complications of XRT. Interleukin-1 (IL-1), in the two forms ¿ and ¿, is the prototypical cytokine involved in virtually every inflammatory response. Exogenous administration of IL-1¿ induces left ventricular systolic dysfunction in the mouse and impairs contractile reserve, reproducing a phenotype of heart failure in experimental models of acute myocardial infarction (AMI). The initial injury induces loss of viable myocardium, which prompts a maladaptive remodeling process (adverse remodeling) characterized by progressive cardiac enlargement and dysfunction, leading to heart failure and cardiac death. Mice with genetic deletion of the IL-1RI have a significantly more favorable profile of cardiac remodeling (less enlargement and dysfunction) following AMI. Both pharmacological and genetic inhibition of IL-1¿ (using recombinant human IL-1Ra [anakinra], IL-1Trap and antibody against IL-1¿) limit the adverse remodeling process, and improve survival. We propose that blocking IL-1 with anakinra may represent a strategy to prevent, limit or treat XRT-induced cardiomyopathy. This proposal has two specific aims. The first is to determine whether increased IL-1 activity (early or late) after XRT exposure contributes to the development of cardiomyopathy in the mouse and whether genetic inhibition of IL-1 signaling can ameliorate the development of XRT-induced cardiomyopathy. The second is to determine whether a pharmacological blockade of IL-1 signaling affects the development of XRT-induced cardiomyopathy in the mouse. Our proposed studies are designed to elucidate the basis for the development of XRT-induced cardiomyopathy with the dual goals of identifying therapeutic strategies for preventing the development of this disease state and rescuing patients in whom the disease would otherwise develop as a consequence of previous radiation treatment.