Schistosome antigen induced modulation of metabolism

血吸虫抗原诱导的代谢调节

• 批准号: 10304040
• 负责人: Keke Celeste Fairfax
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304040
• 关键词: Animal Model; Antiatherogenic; Antidiabetic Drugs; Antigens; Apolipoprotein E; Area; Asthma; Atherosclerosis; Biological Assay; Blood group antigen S; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Chronic; Data; Development; Diabetes Mellitus; Disease; Exposure to; Foundations; Fractionation; Future; Gene Expression Profile; Genus Hippocampus; Glucose Intolerance; Goals; Helminth Antigens; Helminths; High Fat Diet; Immunologics; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Insulin Resistance; Interleukin-4; Knowledge; Laboratories; Legal patent; Lipids; Literature; Mature Bone; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Obesity; Outcome Measure; Parasites; Pathology; Pathway interactions; Phenotype; Population; Prediabetes syndrome; Proteins; Proteomics; Recording of previous events; Regulation; Research; Respiration; Risk; Risk Factors; Role; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Testing; base; chronic inflammatory disease; cytokine; diabetic; diabetic patient; egg; experimental study; extracellular; helminth infection; immunoregulation; in vivo; innovation; lipidome; macrophage; male; metabolic phenotype; metabolic profile; mitochondrial metabolism; mortality; mouse model; new therapeutic target; non-diabetic; novel; programs; protective effect; screening; success; therapy development; transcriptome

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.

项目摘要 在全球范围内，寄生蠕虫感染与糖尿病等代谢性疾病呈负相关， 动脉粥样硬化和肥胖，但寄生虫因素，能够调节代谢疾病， 目前未知。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。 超过65%的糖尿病患者死于心血管并发症， 迫切需要鉴定能够调节胰岛素抵抗、肥胖症和糖尿病的新化合物， 动脉粥样硬化。最近的证据表明，由巨噬细胞驱动的炎症是 与肥胖和胰岛素抵抗相关，而动脉粥样硬化被认为是由脂质驱动的， 依赖性慢性骨髓炎我们的实验室最近发现曼氏血吸虫 感染调节骨髓谱系的代谢转录组，并且这种调节与 在ApoE-/-高脂血症中， 饮食小鼠模型。我们的实验室和其他实验室已经确定，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是未知的。为了填补这些现有的 知识的差距，我们建议进行蛋白质组学分析和筛选，以确定抗原足以 调节巨噬细胞代谢。我们将首先1）鉴定足以调节成熟骨的抗原库 骨髓来源的巨噬细胞代谢，然后2）确定足以编程的抗原亚群 骨髓前体以在体内产生免疫调节的巨噬细胞。从这些生成的数据 这些研究将为进一步了解蠕虫诱导的巨噬细胞在 对全身新陈代谢的长期调节