Innate Inflammatory Control of Cachexia

项目摘要 恶病质，或瘦体重的炎症性损失，是慢性病发病率的主要预测指标。 恶病质是一种病因复杂的疾病，已被证明很难在动物身上建立模型。人们对此知之甚少 控制恶病质发病、持续和病理的分子机制；广泛有效 缺乏扭转恶病质的干预措施。我们最近发现，小鼠体内的弓形虫感染 研究持续性恶病质的新动物模型。这种模式的长寿导致了人们发现 慢性恶病质小鼠的肝脏有血管周围纤维化。重要的是，我们发现老鼠有缺陷 在IL-1先天免疫信号通路中，可以防止恶病质、纤维化和脂质改变 新陈代谢，尽管含有与WT动物相似的弓形虫滴度。我们假设恶病质是 长期使用IL-1信号的成本。在这项提案中，我们将确定是消除慢性感染还是 阻断纤维化足以逆转恶病质。我们将确定导致恶病质的IL-1R表达细胞类型 并确定成纤维细胞和/或内皮细胞上的IL-1信号如何控制异常的脂代谢 恶病质肝脏。我们的研究是及时的，因为最近的一项临床研究表明，用 一种单抗已经扭转了恶病质的一些症状。因此，我们有了一个新的模型来理解 IL-1在恶病质中的作用机制和疾病逆转的治疗干预试验。理解 IL-1轴在恶病质中的作用将提高患者的寿命和舒适度 令人衰弱的慢性疾病。

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.