Insulin regulation of lymphatic vessel integrity

胰岛素对淋巴管完整性的调节

• 批准号: 10683800
• 负责人: Vincenza Cifarelli
• 金额: $ 36.65万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683800
• 关键词: Ablation; Address; Adipose tissue; Affect; Blood; Blood Vessels; CD36 gene; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Data; Defect; Dendritic Cells; Development; Dietary Intervention; Endocytosis; Endothelial Cells; Endothelium; Fatty Acids; Gatekeeping; Genes; Goals; Guanosine Triphosphate Phosphohydrolases; Gut Mucosa; Health; Heterogeneity; Homeostasis; Immune; Immunity; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intercellular Junctions; Intestines; Lead; Lipids; Liquid substance; Lymph; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Maintenance; Mediating; Membrane; Mesentery; Metabolic; Metabolic Diseases; Modeling; Molecular; Mucosal Immunity; Mus; Neuropilin-1; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Outcome; Palmitates; Permeability; Phenotype; Physiological; Post-Translational Protein Processing; Proteins; Proteomics; Regulation; Risk Factors; Role; Signal Pathway; Signal Transduction; Testing; Tissue Expansion; Tissues; Ubiquitination; Vascular Endothelium; Vascular remodeling; Visceral; cadherin 5; caveolin 1; cell type; clinical translation; commensal microbes; endothelial dysfunction; fatty acid oxidation; improved; in vivo; insulin regulation; insulin signaling; lipid metabolism; lipid transport; lymphatic development; lymphatic dysfunction; lymphatic valve; lymphatic vessel; mesenteric lymph node; microbial; microbiota; mouse model; novel; palmitoylation; protein function; recruit; trafficking; translocase

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.

项目概要/摘要 淋巴管的完整性可以维持器官功能和保护性免疫力。脂质的作用 淋巴管发育和维持中的代谢现在正在兴起，但对于脂质如何影响淋巴管发育和维持知之甚少。 环境调节淋巴管的完整性。脂质和胰岛素信号传导与异常内皮细胞相关 但淋巴管中脂质和胰岛素信号传导的目标尚未得到充分研究。脂质影响内皮细胞 通过蛋白质修饰（例如脂化）保持细胞稳态。新兴研究表明胰岛素 调节与血管完整性和重塑相关的蛋白质的内皮脂化。是否有此规定 适用于淋巴起源的内皮细胞仍有待探索。淋巴内皮细胞具有较高的 对胰岛素的敏感性高于血液内皮细胞，但生理相关性仍不清楚。淋巴管 内皮胰岛素抵抗可能会损害 LEC 稳态和功能，但体内验证是 临床转化的前景是必要的。 我们的研究表明，脂质易位酶 CD36 在收集淋巴管中的表达出人意料地较高。 船只。淋巴管内皮细胞中 CD36 的缺失会损害血管完整性并导致多器官损伤 内皮功能障碍的典型炎症。胰岛素和 CD36 在许多细胞类型中相互调节。我们 假设胰岛素介导的 CD36 翻译后修饰和周转调节 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 以及胰岛素信号传导受损对淋巴管功能障碍的影响。我们将确定新的目标 胰岛素介导的淋巴管脂质化的研究，并解决 CD36 的缺失是否会扭曲表型和 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管之间的串扰 血管功能和共生微生物群，并揭示功能失调的器官特异性和系统性影响 淋巴管。然后我们将评估微生物群的短暂消融或饮食干预是否可以改善 淋巴完整性，可以改善代谢结果和炎症。