Netrin-1 in Metabolic and Inflammatory Crosstalk in Cardiometabolic Disease

摘要-项目2 心血管疾病仍然是全球主要的死亡原因，动脉粥样硬化是主要原因。 贡献者。肥胖症及其并发症，包括糖尿病和非酒精性脂肪肝的持续增加 疾病，进一步增加动脉粥样硬化的风险。虽然这种心脏代谢性疾病曾经被认为是 主要是由于脂类代谢的失调，现在认识到对过量脂类的免疫反应 组织(动脉、脂肪组织、肝脏)影响心脏代谢性疾病的进展及其并发症。 确定这种破坏性代谢性炎症的潜在机制，并确定治疗方法 遏制它的方法，是我们的计划项目赠款(PPG)的主要重点。在它的第一个周期，我们的PPG 揭示巨噬细胞代谢、运输和组织特异性改变的关键途径 分子重编程导致慢性炎症，从而导致动脉粥样硬化和代谢紊乱 这加速了它(例如，肥胖和非酒精性脂肪性肝炎；非酒精性脂肪性肝炎)。通过对小鼠模型的检查 和来自这些疾病患者的人体组织，项目2研究指出了致病作用 神经免疫导向分子Netrin-1在指导未消退炎症和脂质堆积中的作用 新陈代谢组织。我们假设netrin-1参与了Mø代谢和转运的失调， 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- 导致心脏代谢性疾病的特定刺激。PPG第一周期中的关键项目2发现 包括：(1)髓系细胞中Netrin-1的缺失可以保护小鼠免受高脂饮食诱导的肥胖和肝脏的损伤 (2)Netrin-1的表达改变了Mø的功能轨迹 在肥胖脂肪组织和动脉粥样硬化斑块中；以及(3)不同亚型的netrin-1在莫氏体内积聚。 在代谢性炎症期间，这可能会同时引发受体依赖和非受体依赖的信号。在这 提案中，我们将研究莫氏衍生的netrin-1如何通过两者促进动脉粥样硬化、肥胖和NASH 内源性和外源性机制，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性疾病的目标。 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的交流。 通过共享的工具、战略和生物信息学方法，并测试与治疗相关的方法 阻止其有害行为。 通过人体组织和转录组的互补检查而得到加强 数据库，我们将使用最先进的RNA测序，结合空间转录，以产生 以及“可视化”推测的相互作用体和上游转录调控因子的综合图谱 调节心脏代谢紊乱的器官内和器官间串扰。这项工作和计划项目举行 通过晶状体确定动脉粥样硬化、肥胖症和NASH的有针对性和谨慎的治疗方法的希望很大 代谢器官网络中异常调节的巨噬细胞诱发的通讯。

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.