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

基本信息

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
项目类别：
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

项目摘要

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 心血管疾病仍然是全世界死亡的主要原因，其中动脉粥样硬化是一个主要原因肥胖及其并发症（包括糖尿病和非酒精性脂肪肝）的不断增加。疾病，进一步增加动脉粥样硬化的风险，而此类心脏代谢疾病曾经被归因于。主要是由于脂质代谢失调，现在人们认识到，对过量脂质的免疫反应组织（动脉、脂肪组织、肝脏）决定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机制，并确定治疗方法消除它的方法是我们的计划项目拨款（PPG）的主要重点。在第一个周期中，我们的PPG。揭示了巨噬细胞（Mø）代谢、运输和组织特异性改变的关键途径分子重编程会导致慢性炎症，从而加剧动脉粥样硬化和代谢紊乱加速它的发生（例如，肥胖和非酒精性脂肪性肝炎；NASH）。以及来自患有这些疾病的患者的人体组织，项目 2 研究指出了这些疾病的致病作用神经免疫指导分子 netrin-1 指导非消退性炎症和脂质积累我们认为 netrin-1 会导致 Mø 代谢和运输失调，和炎症的分子重新编程，并且这些过程是由组织和环境驱动的 PPG 第 1 周期中关键项目 2 的发现导致心脏代谢疾病。包括：（1）删除骨髓细胞中的netrin-1可以保护小鼠免受高脂饮食引起的肥胖和肝病的影响 (2) Netrin-1 表达改变 Mø 的功能轨迹；在肥胖脂肪组织和动脉粥样硬化斑块中；(3) 不同的 netrin-1 亚型在 Mø 中积累在代谢炎症过程中，可以激发受体依赖性和非依赖性信号传导。提案中，我们将研究 Mø 衍生的 netrin-1 如何通过这两种途径促进动脉粥样硬化、肥胖和 NASH Mø 内在和外在机制，包括与其他免疫细胞和实质细胞的串扰，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，我们将探讨 netrin-1 如何促进器官内和器官间通讯通过共享工具、策略和生物信息学方法，并测试治疗相关方法阻止其求救行动。通过人体组织和转录组的补充检查得到强化数据库，我们将采用最先进的 RNA 测序，结合空间转录组学，生成并“可视化”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的串扰。这项工作和该计划项目正在进行。通过镜头确定动脉粥样硬化、肥胖和 NASH 的靶向和审慎疗法的巨大希望代谢器官网络中巨噬细胞诱发的通讯失调。