Innate Inflammatory Control of Cachexia

恶病质的先天炎症控制

• 批准号: 10028888
• 负责人: Sarah E. Ewald
• 金额: $ 39.45万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028888
• 关键词: Animal Model; Animals; Automobile Driving; Cachexia; Chronic; Chronic Disease; Clinical Research; Complex; Disease; Endothelial Cells; Etiology; Fatigue; Fibroblasts; Fibrosis; Functional disorder; Human; Immune signaling; Infection; Inflammatory; Interleukin-1; Intervention; Lipids; Liver; Longevity; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Pain; Pathology; Patients; Perivascular Fibrosis; Role; Signal Pathway; Signal Transduction; Symptoms; Taxes; Therapeutic Intervention; Time; Toxoplasma; cell type; chronic infection; combat; cost; improved; lean body mass; lipid metabolism; mortality; novel; novel therapeutics; therapeutic evaluation; tool

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.

项目摘要 恶病质或瘦体重的炎症丧失是慢性疾病中发病率的主要预测指标。 病原体是一种复杂的病因疾病，被证明很难在动物中建模。关于 控制恶病质发作，持久性和病理的分子机制；并广泛有效 缺乏反向恶病质的干预措施。我们最近表明，小鼠的弓形虫感染是 新的动物模型研究持续的恶病质。该模型的寿命导致发现 长期缓存小鼠的肝脏中血管周围纤维化。重要的是，我们发现小鼠有缺陷 在IL-1先天免疫信号通路中，可以保护恶病质和纤维化和脂质改变 新陈代谢，尽管具有类似的弓形虫作类似的弓形虫。我们假设恶病质是 长期IL-1信号传导的成本。在此提案中，我们将确定是否消除了慢性感染或 阻塞纤维化足以逆转缓存。我们将确定驱动恶病质的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信号传导如何控制异常的脂质代谢 缓存肝。我们的研究是及时的，因为最近的一项临床研究表明，用 单克隆抗体逆转了恶病质的一些症状。因此，我们有一个新颖的模型可以理解 IL-1功能在恶病质和测试疾病逆转的治疗干预措施中的机制。理解 IL-1轴在恶病质中的作用将改善患有广泛范围的患者的寿命和舒适性 使人衰弱的慢性疾病。