Insulin regulation of lymphatic vessel integrity

项目总结/摘要 淋巴管的完整性能够维持器官功能和保护性免疫。脂质的作用 淋巴发育和维持中的代谢现在正在出现，但对脂质如何在淋巴细胞中代谢的了解较少。 环境调节淋巴管完整性。脂质和胰岛素信号与异常内皮细胞 但是脂质和胰岛素信号转导的靶点还没有得到充分的研究。脂质影响内皮细胞 通过蛋白质修饰如脂化来实现细胞内稳态。新的研究表明，胰岛素 调节与血管完整性和重塑相关的蛋白质的内皮脂质化。这一规定是否 应用于淋巴起源的内皮细胞仍然未被探索。淋巴管内皮细胞具有较高的 胰岛素敏感性高于血液内皮细胞，但生理相关性尚不清楚。淋巴 内皮胰岛素抵抗可能损害LEC的稳态和功能，然而，在体内验证， 在临床翻译的前景中是必要的。 我们的研究表明，在收集淋巴结中，脂质移位酶CD 36的表达出乎意料的高， 船舶.淋巴管内皮细胞中CD 36的缺失损害血管完整性并导致多器官 内皮功能障碍典型炎症。胰岛素和CD 36在许多细胞类型中相互调节。我们 假设胰岛素介导的CD 36翻译后修饰和转换调节 淋巴管完整性。为了实现这一目标，我们的目标是研究淋巴管完整性的新调节 以及受损的胰岛素信号传导对功能失调的淋巴管的作用。我们将确定新的目标 胰岛素介导的脂质化在淋巴管中的作用，并解决CD 36的丢失是否会影响表型和 肠系膜集合血管中LEC亚群的功能异质性促进炎症， 促纤维化和代谢异常表型。我们的研究将揭示淋巴细胞之间的相互作用 血管功能和肠道微生物群，并揭示功能障碍的器官特异性和全身性影响 反物质。然后，我们将评估微生物群的短暂消融或饮食干预是否会改善 淋巴完整性，并可以改善代谢结果和炎症。

PROJECT SUMMARY/ABSTRACT Integrity of lymphatic vessels enables maintenance of organ function and protective immunity. The role of lipid metabolism in lymphatic development and maintenance is now emerging, but less is known about how the lipid milieu regulates lymphatic vessel integrity. Lipid and insulin signaling are associated with abnormal endothelial function but targets of lipid and insulin signaling in the lymphatics are understudied. Lipids affect endothelial cellular homeostasis through protein modifications such as lipidation. Emerging studies show that insulin regulates endothelial lipidation of proteins relevant to vascular integrity and remodeling. Whether this regulation applies to endothelial cells of lymphatic origin remain unexplored. Lymphatic endothelial cells have higher sensitivity to insulin than blood endothelial cells but physiological relevance remains unclear. Lymphatic endothelial insulin resistance could impair LEC homeostasis and function, however in vivo verification is necessary in the prospect of clinical translation. Our studies showed an unexpected higher expression of the lipid translocase CD36 in collecting lymphatic vessels. Loss of CD36 in lymphatic endothelial cells compromises vessel integrity and causes multi-organ inflammation typical of endothelial dysfunction. Insulin and CD36 are mutually regulated in many cell types. We hypothesize that insulin-mediated regulation of CD36 post-translational modifications and turnover regulates lymphatic vessel integrity. Toward this goal, we aim to examine the novel regulation of lymphatic vessel integrity and the contribution of impaired insulin signaling to dysfunctional lymphatic vessels. We will identify new targets of insulin-mediated lipidation in lymphatic vessels and address whether loss of CD36 skews phenotypic and functional heterogeneity of LEC subsets in the mesenteric collecting vessels promoting an inflammatory, profibrotic, and metabolically abnormal phenotype. Our study will uncover the cross-talk between lymphatic vascular function and commensal microbiota, and reveal organ-specific and systemic effects of dysfunctional lymphatics. We will then evaluate whether transient ablation of the microbiota, or dietary intervention improves lymphatic integrity and could ameliorate metabolic outcomes and inflammation.