Schistosome antigen induced modulation of metabolism

项目摘要 在全球范围内，寄生虫感染与代谢性疾病，如糖尿病， 动脉粥样硬化和肥胖，但能够调节代谢性疾病的寄生虫因素是 目前尚不清楚。糖尿病患者患心血管疾病的可能性是非糖尿病患者的两倍 疾病，超过65%的糖尿病患者死于心血管并发症，因此有 迫切需要确定能够调节胰岛素抵抗、肥胖和 这一人群中的动脉粥样硬化。最近的证据表明，巨噬细胞驱动的炎症是 与肥胖和胰岛素抵抗有关，而动脉粥样硬化被认为是由脂质- 依赖型慢性髓系炎症。我们实验室最近鉴定出曼氏血吸虫 感染调节髓系细胞的代谢转录组，并且这种调节是相关的 具有预防胰岛素抵抗、糖尿病和动脉粥样硬化的作用 节食小鼠模型。我们的实验室和其他实验室已经证实，体内代谢保护依赖于 暴露于鸡蛋抗原，但足以提供保护的抗原尚不清楚。为了填补这些电流 知识缺口，我们建议进行蛋白质组分析和筛选，以确定足以 调节巨噬细胞新陈代谢。我们将首先确定足以调节成熟骨骼的抗原池 骨髓来源的巨噬细胞代谢，然后2)确定足以编程的抗原亚集 体内产生免疫调节巨噬细胞的骨髓前体细胞。从这些数据中产生的数据 这些研究将为进一步了解蠕虫诱导的巨噬细胞在体内的作用奠定基础 全身代谢的长期调节。

Project Summary Globally, parasitic helminth infections inversely correlate with metabolic diseases, such as diabetes, atherosclerosis, and obesity, but the parasite factors that are capable of modulating metabolic disease are currently unknown. Diabetic patients are twice as likely as non-diabetic individuals to develop cardiovascular disease, with more than 65% of diabetic patients dying from cardiovascular complications, thus there is a critical need for identifying novel compounds capable of modulating insulin resistance, obesity, and atherosclerosis in this population. Recent evidence has suggested that inflammation driven by macrophages is associated with both obesity and insulin resistance, while atherosclerosis is accepted to be driven by lipid- dependent chronic myeloid inflammation. Our laboratory has recently identified that Schistosoma mansoni infection modulates the metabolic transcriptome of the myeloid lineage, and that this modulation is correlated with protection from the development of insulin resistance, diabetes, and atherosclerosis in the ApoE-/- high fat diet mouse model. Our lab and others have established that in vivo metabolic protection is dependent on exposure to egg antigens, but the antigens sufficient to confer protection are unknown. To fill these current knowledge gaps, we propose to perform proteomic analysis and screening to identify the antigens sufficient to modulate macrophage metabolism. We will first 1) identify pools of antigens sufficient to modulate mature bone marrow derived macrophage metabolism, and then 2) determine the subset of antigens sufficient to program bone marrow precursors to generate immunomodulated macrophages in vivo. The data generated from these studies will lay the foundation for future studies on understanding the role of helminth induced macrophages in the long-term regulation of whole-body metabolism.