Durable Schistosome induced metabolic alterations to the myeloid lineage

持久的血吸虫诱导骨髓谱系的代谢改变

• 批准号: 10184936
• 负责人: Eyal Amiel
• 金额: $ 62.7万
• 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: 2021-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10184936
• 关键词: Address; Anti-Inflammatory Agents; Antiatherogenic; Antigens; Apolipoprotein E; Area; Asthma; Atherosclerosis; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Cholesterol Homeostasis; Chronic; Data; Dependence; Development; Diabetes Mellitus; Differentiation Antigens; Disease; Estrogens; Female; Formulation; Genetic; Genetic Transcription; Genomics; Glucose Intolerance; Goals; Gonadal Steroid Hormones; Helminths; Hepatic; High Fat Diet; Immunologics; Infection; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Insulin; Insulin Resistance; Interleukin-4; Lead; Link; Lipids; Literature; Macrophage Activation; Maps; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Modification; Morbidity - disease rate; Mus; Myelogenous; Myeloid Progenitor Cells; Nematoda; Obesity; Oxygen Consumption; Pathology; Pathway interactions; Patients; Phenotype; Phospholipid Metabolism; Phospholipids; Population; Principal Component Analysis; Progesterone; Recording of previous events; Research; Resolution; Risk; Risk Factors; Role; Schistosoma; Schistosoma mansoni; Testing; Testosterone; Transcription Alteration; amino acid metabolism; biological sex; cardiovascular disorder risk; chronic inflammatory disease; cytokine; diabetic; diabetic patient; helminth infection; hematopoietic differentiation; immune function; immunoregulation; innovation; insulin sensitivity; macrophage; male; monocyte; mortality; mouse model; non-diabetic; novel; novel strategies; progenitor; protective effect; respiratory; stem cell niche; success; therapy development; transcriptome; transcriptomics

PROJECT SUMMARY Diabetic patients have a two-fold greater risk of developing cardiovascular disease than non-diabetic subjects, and more than 65% of diabetic patients die from cardiovascular complications, thus, there is a critical need for novel approaches to targeting insulin resistance, obesity, and atherosclerosis in this population. Recent evidence has suggested that innate and/or adaptive inflammatory responses are associated with both insulin resistance and obesity, while atherosclerosis is now widely accepted to be a lipid-dependent chronic inflammatory disease. An increasing body of literature has established an inverse correlation between chronic helminth infections and metabolic syndrome/diabetes. The central hypothesis of this project is that schistosome antigenic exposure induces long-lived modifications in the monocyte/macrophage lineage that lead to profound alterations in systemic phospholipid, cholesterol, and amino acid metabolism, resulting in a protective state from the detrimental effects of High Fat Diet (HFD) (e.g., insulin insensitivity, and atherosclerosis). The rationale for this research is that identifying genetic drivers that underlie this protective phenotype is expected to enable the formulation and development of therapies to target these pathways as treatments for diabetic patients at risk for CVD. This objective will be addressed by pursuing three specific aims: 1) Define the role of S. mansoni infection in regulating the long-term metabolic and immunological function of macrophages; 2) Determine how S. mansoni infection regulates hematopoietic differentiation of macrophages at the transcriptional level; and 3) Determine the role of biological sex and sex hormones in schistosome induced metabolic reprogramming. It is expected that the findings from these studies will provide a definitive conceptual framework as to the mechanism through which S. mansoni infection modulates metabolism and immunologic plasticity of the macrophage lineage.

项目摘要 糖尿病患者发生心血管疾病的风险比非糖尿病受试者高两倍， 超过65%的糖尿病患者死于心血管并发症，因此，迫切需要 针对这一人群的胰岛素抵抗、肥胖和动脉粥样硬化的新方法。最近 有证据表明，先天性和/或适应性炎症反应与胰岛素抵抗和炎症反应有关。 抵抗和肥胖，而动脉粥样硬化现在被广泛认为是一种脂质依赖性慢性疾病， 炎症性疾病。越来越多的文献已经建立了慢性病与慢性病之间的负相关关系。 寄生虫感染和代谢综合征/糖尿病。这个项目的核心假设是， 溶酶体抗原暴露诱导单核细胞/巨噬细胞谱系中的长寿命修饰， 导致系统性磷脂、胆固醇和氨基酸代谢的深刻改变， 保护状态免受高脂肪饮食（HFD）的有害影响（例如，胰岛素不敏感，和 动脉粥样硬化）。这项研究的基本原理是，确定这种保护性的遗传驱动因素， 表型的研究有望使靶向这些途径的疗法的制定和开发成为可能， 治疗有CVD风险的糖尿病患者。为实现这一目标，将采取三项具体措施： 目的：1）明确S的角色;曼氏菌感染对机体长期代谢和免疫的调节作用 2）确定S. mansoni感染调节造血分化 在转录水平上的巨噬细胞;和3）确定生物性和性激素在 染色体诱导的代谢重编程。预计这些研究的结果将提供 一个明确的概念框架，通过该机制，S。曼氏感染调节 代谢和免疫可塑性的巨噬细胞谱系。