Schistosome antigen induced modulation of metabolism

血吸虫抗原诱导的代谢调节

基本信息

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
项目类别：
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

项目摘要

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，寄生虫的蠕虫感染与代谢性疾病（例如糖尿病）成反比动脉粥样硬化和肥胖症，但是能够调节代谢疾病的寄生虫因素是目前未知。糖尿病患者发展心血管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，因此有一个识别能够调节胰岛素抵抗，肥胖和该人群的动脉粥样硬化。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，而动脉粥样硬化被接受为脂质驱动依赖的慢性髓样炎症。我们的实验室最近确定感染调节髓样谱系的代谢转录组，并且该调节是相关的防止胰岛素抵抗，糖尿病和动脉粥样硬化的抗性 - / - 高脂肪饮食鼠标模型。我们的实验室和其他实验室已经确定，体内代谢保护取决于暴露于鸡蛋抗原，但足以提供保护的抗原尚不清楚。填充这些电流知识差距，我们建议进行蛋白质组学分析和筛查，以识别足够的抗原调节巨噬细胞代谢。我们将首先1）确定足以调节成熟骨骼的抗原池骨髓衍生的巨噬细胞代谢，然后2）确定足以编程的抗原的子集骨髓前体在体内产生免疫调节的巨噬细胞。从这些产生的数据研究将为未来的研究奠定有关了解蠕虫诱导巨噬细胞在全身代谢的长期调节。