Netrin-1 in Metabolic and Inflammatory Crosstalk in Cardiometabolic Disease

Netrin-1 在心脏代谢疾病代谢和炎症串扰中的作用

• 批准号: 10424905
• 负责人: KATHRYN J MOORE
• 金额: $ 50.85万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424905
• 关键词: Adipocytes; Adipose tissue; Antisense Oligonucleotides; Arterial Fatty Streak; Arteries; Atherosclerosis; Biogenesis; Bioinformatics; Blocking Antibodies; CD4 Positive T Lymphocytes; Cardiometabolic Disease; Cardiovascular Diseases; Cause of Death; Cell Communication; Cell Nucleus; Cell physiology; Cells; Chronic; Communication; Complement 1q; Coupled; Cytoskeletal Modeling; Data; Databases; Deposition; Diabetes Mellitus; Diet; Disease; Disease Progression; Environment; Fatty Liver; Fibrosis; Fostering; Functional disorder; Genetic; Genetic Models; Genetic Transcription; Glucans; Goals; High Fat Diet; Human; Immune; Immune response; In Vitro; Inflammation; Inflammation Process; Inflammatory; Insulin Resistance; Intervention; Link; Lipids; Liver; Maps; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Molecular; Monoclonal Antibodies; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; NTN1 gene; Neuroimmune; Obesity; Organ; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Population; Process; Program Research Project Grants; Protein Isoforms; Regulation; Resolution; Ribosomes; Role; Rupture; Shapes; Signal Transduction; Stimulus; T cell differentiation; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissue Expansion; Tissue Transplantation; Tissues; Training; Translations; Up-Regulation; Work; atherosclerosis risk; comorbidity; diet-induced obesity; extracellular; human tissue; in vivo; inhibitor; lens; lipid metabolism; liver inflammation; macrophage; mouse model; neogenin; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; particle; programs; receptor; recruit; response; single-cell RNA sequencing; therapeutic evaluation; tool; trafficking; transcriptome; transcriptome sequencing; transcriptomics

Summary – Project 2 Cardiovascular disease remains the leading cause of death worldwide, with atherosclerosis being a major contributor. The unremitting rise in obesity and its co-morbidities, including diabetes and non-alcoholic fatty liver diseases, further increase the risk of atherosclerosis. While such cardiometabolic diseases were once attributed primarily to dysregulations of lipid metabolism, it is now appreciated that the immune response to excess lipid in tissues (artery, adipose tissue, liver) shapes cardiometabolic disease progression and its complications. Determining the mechanisms underlying this damaging metabolic inflammation, and identifying therapeutic approaches to quench it, are major focuses of our Program Project Grant (PPG). In its first cycle, our PPG unveiled key pathways through which alterations in macrophage (Mø) metabolism, trafficking, and tissue-specific molecular reprogramming drive the chronic inflammation that fuels atherosclerosis, and the metabolic disorders that accelerate it (e.g., obesity and non-alcoholic steatohepatitis; NASH). Through examination of mouse models and human tissues from patients with these disorders, Project 2 studies point to pathogenic roles for the neuroimmune guidance molecule netrin-1 in directing non-resolving inflammation and lipid accumulation in metabolic tissues. We hypothesize that netrin-1 contributes to dysregulation of Mø metabolism and trafficking, and molecular re-programming of inflammation, and that these processes are driven by tissue- and environment- specific stimuli that contribute to cardiometabolic disease. Key Project 2 discoveries in cycle 1 of the PPG include: (1) Deletion of netrin-1 in myeloid cells protects mice from high fat diet-induced obesity and hepatic steatosis, and regresses advanced atherosclerosis; (2) Netrin-1 expression alters the functional trajectory of Mø in obese adipose tissue and atherosclerotic plaques; and (3) Distinct isoforms of netrin-1 accumulate in Mø during metabolic inflammation that can provoke both receptor-dependent and -independent signaling. In this proposal, we will investigate how Mø-derived netrin-1 promotes atherosclerosis, obesity and NASH through both Mø-intrinsic and -extrinsic mechanisms, including cross-talk with other immune cells and parenchymal cells, and how interventions targeting netrin-1 can be leveraged toward our goal of mitigating cardiometabolic disease. Together with Projects 1 and 3, we will probe how netrin-1 contributes to intra- and inter-organ communications through shared tools, strategies and bioinformatics approaches, and test therapeutically relevant approaches to block its detrimental actions. Fortified by complementary examinations in human tissues and transcriptome databases, we will employ state-of-the-art RNA sequencing, coupled with spatial transcriptomics, to generate and “visualize” a comprehensive map of the putative interactome and upstream transcriptional regulators that regulate intra- and interorgan cross-talk in cardiometabolic disorders. This work and the Program Project hold great promise to identify targeted and prudent therapies in atherosclerosis, obesity and NASH through the lens of dysregulated macrophage-evoked communications in metabolic organ networks.

摘要-项目2 心血管疾病仍然是世界范围内的主要死亡原因，动脉粥样硬化是主要的 贡献者。肥胖及其并发症的持续增加，包括糖尿病和非酒精性脂肪肝 疾病，进一步增加动脉粥样硬化的风险。虽然这种心脏代谢疾病曾经被认为是 主要是脂质代谢失调，现在认识到， 组织（动脉、脂肪组织、肝脏）塑造心脏代谢疾病的进展及其并发症。 确定这种破坏性代谢炎症的潜在机制，并确定治疗方法， 解决这一问题的方法，是我们计划项目资助（PPG）的主要重点。在第一个周期，我们的PPG 揭示了巨噬细胞（MMPs）代谢、运输和组织特异性 分子重编程驱动慢性炎症，引发动脉粥样硬化和代谢紊乱 使其加速（例如，肥胖和非酒精性脂肪性肝炎; NASH）。通过对小鼠模型的检查 和人体组织，项目2的研究指出，致病作用，为这些疾病的患者， 神经免疫导向分子netrin-1在引导非消退性炎症和脂质积聚中的作用 代谢组织我们假设netrin-1有助于MMPs代谢和运输的失调， 以及炎症的分子重新编程，这些过程是由组织和环境驱动的， 导致心脏代谢疾病的特定刺激。PPG第1周期的关键项目2发现 包括：（1）髓系细胞中netrin-1缺失可保护小鼠免受高脂饮食诱导的肥胖和肝脏损伤 （2）Netrin-1的表达改变了MMPs的功能轨迹 在肥胖脂肪组织和动脉粥样硬化斑块中;和（3）netrin-1的不同亚型在MMPs中积累 在代谢性炎症过程中，可以激发受体依赖性和非依赖性信号传导。在这 我们将研究MMPs衍生的netrin-1如何通过两者促进动脉粥样硬化、肥胖和NASH。 免疫-内在和外在机制，包括与其他免疫细胞和实质细胞的相互作用，以及 如何利用针对netrin-1的干预措施来实现我们减轻心脏代谢疾病的目标。 与项目1和3一起，我们将探索netrin-1如何促进器官内和器官间的通信 通过共享工具、战略和生物信息学方法，并测试治疗相关方法， 阻止其有害行为。 通过人体组织和转录组中的补充检查进行强化 数据库，我们将采用最先进的RNA测序，再加上空间转录组学，以产生 并"可视化"一个假定的相互作用组和上游转录调节因子的综合图谱， 调节心脏代谢紊乱中的器官内和器官间串扰。这项工作和计划项目举行 通过透镜确定动脉粥样硬化、肥胖和NASH的靶向和谨慎治疗的巨大希望 代谢器官网络中巨噬细胞诱发的通讯失调。