Innate Inflammatory Control of Cachexia

项目摘要 恶病质或瘦体重的炎症性损失是慢性疾病发病率的主要预测因素。 恶病质是一种病因复杂的疾病，已证明难以在动物中建模。关于这一点，我们知之甚少。 控制恶病质发作、持续和病理的分子机制;并且广泛有效 缺乏逆转恶病质的干预措施。我们最近发现，小鼠弓形虫感染是 研究持续性恶病质的新动物模型。这个模型的长期存在使我们发现， 慢性恶病质小鼠在肝脏中具有血管周围纤维化。重要的是，我们发现有缺陷的老鼠 在IL-1先天免疫信号传导途径中， 尽管携带与WT动物相似的弓形虫滴度，但在代谢方面，我们假设恶病质是 长期IL-1信号传导的代价。在这项提案中，我们将确定是否消除慢性感染或 阻断纤维化足以逆转恶病质。我们将确定驱动恶病质的IL-1 R表达细胞类型 并确定成纤维细胞和/或内皮细胞上的IL-1信号传导如何控制在糖尿病中的异常脂质代谢。 恶病质的肝脏我们的研究是及时的，因为最近的临床研究表明，用 一种单克隆抗体已经逆转了恶病质的某些症状。因此，我们有一个新的模型来理解 IL-1在恶病质中的作用机制和测试疾病逆转的治疗干预。理解 IL-1轴在恶病质中的作用将改善患者的寿命和舒适度， 慢性疾病的威胁

Project Summary Cachexia, or the inflammatory loss of lean body mass, is a leading predictor of morbidity across chronic diseases. A disease of complex etiology, cachexia has proven difficult to model in animals. Little is known regarding the molecular mechanisms controlling cachexia onset, persistence and pathology; and widely efficacious interventions to reverse cachexia are lacking. We have recently shown that Toxoplasma infection in mice is novel animal model to study sustained cachexia. The longevity of this model has led to the discovery that chronically cachectic mice have perivascular fibrosis in the liver. Importantly, we have found that mice defective in the IL-1 innate immune signaling pathway are protected from cachexia and fibrosis and altered lipid metabolism, despite harboring a similar titer of Toxoplasma as WT animals. We hypothesize that cachexia is a cost of long-term IL-1 signaling. In this proposal we will determine whether eliminating chronic infection or blocking fibrosis is sufficient to reverse cachexia. We will identify the IL-1R expressing cell types driving cachexia and determine how IL-1 signaling on fibroblasts and/or endothelial cells control aberrant lipid metabolism in cachectic livers. Our studies are timely, as a recent clinical study demonstrated that blocking human IL-1a with a monoclonal antibody has reversed some symptoms of cachexia. Thus, we have a novel model to understand the mechanism of IL-1 function in cachexia and test therapeutic interventions for disease reversal. Understanding the role of the IL-1 axis in cachexia will improve the life span and comfort of patients suffering from a wide range of debilitating chronic diseases.