Protection from Radiation Induced Cardiomyopathy

描述（由申请方提供）：在各种恶性肿瘤的放射治疗（XRT）背景下可能发生心脏放射损伤。 虽然最初的（急性）心脏损伤 随着癌症治疗的日益成功，更多先前接受过XRT的患者将具有正常（或接近正常）的预期寿命，并且现在可能处于XRT的长期并发症的风险中。 白细胞介素-1（IL-1），有<$和<$两种形式，是参与几乎所有炎症反应的原型细胞因子。 外源性给予IL-1可诱导小鼠左心室收缩功能障碍并损害收缩储备，在急性心肌梗死（AMI）实验模型中再现心力衰竭表型。 初始损伤诱导存活心肌的丧失，这促使以进行性心脏增大和功能障碍为特征的适应不良重构过程（不良重构），导致心力衰竭和心源性死亡。 具有IL-1 RI基因缺失的小鼠在AMI后具有显著更有利的心脏重塑特征（较小的增大和功能障碍）。 IL-1 <$的药理学和遗传学抑制（使用重组人IL-1 Ra [阿那白滞素]，IL-1 Trap和抗IL-1 <$的抗体）限制了不良重塑过程，并提高了生存率。 我们认为用阿那白滞素阻断IL-1可能是预防、限制或治疗XRT诱导的心肌病的一种策略。 这项建议有两个具体目标。 首先是确定是否增加IL-1活性（早期或晚期）后， XRT暴露有助于小鼠心肌病的发生，以及IL-1信号传导的遗传抑制是否可以改善XRT诱导的心肌病的发生。第二个是确定IL-1信号传导的药理学阻断是否影响小鼠中XRT诱导的心肌病的发展。 我们提出的研究旨在阐明XRT诱导的心肌病发展的基础，其双重目标是确定预防这种疾病状态发展的治疗策略，并挽救因既往放射治疗而发展为疾病的患者。

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.