Site-1 protease-mediated lipid metabolism in lymphatic vascular development

位点 1 蛋白酶介导的淋巴血管发育中的脂质代谢

• 批准号: 10400114
• 负责人: Lijun Xia
• 金额: $ 43.7万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400114
• 关键词: Address; Anabolism; Apoptosis; Blood; Blood Vessels; Cardinal vein; Cell membrane; Cells; Cellular Metabolic Process; Cholesterol; Cholesterol Homeostasis; Complement; Data; Defect; Development; Diabetes Mellitus; Dietary Fats; Dorsal; Embryonic Development; Endothelial Cells; Endothelium; Exhibits; Feedback; Genes; Genetic Transcription; Glutamine; Glycolysis; Golgi Apparatus; Human; Immune; Impairment; Infection; Inflammation; Intercellular Fluid; KDR gene; Knowledge; Lead; Lipids; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphedema; Malignant Neoplasms; Mediating; Membrane; Metabolic Pathway; Metabolism; Modeling; Mus; Mutant Strains Mice; Names; Neoplasm Metastasis; Obesity; Operative Surgical Procedures; Pathology; Peptide Hydrolases; Phenotype; Physiological; Primary Lymph Sac; Process; Proliferating; Reporting; Research; Role; SRE-2 binding protein; Serine Protease; Signal Transduction; Site; Skin; Structure; Testing; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Vascular System; Wild Type Mouse; absorption; base; cell growth; cholesterol biosynthesis; driving force; early embryonic stage; experimental study; fatty acid oxidation; immune function; in vitro Assay; in vivo; inhibitor; insight; knock-down; lipid metabolism; lymphatic development; lymphatic vasculature; lymphatic vessel; migration; mouse development; mutant; novel; novel therapeutics; rapid growth; receptor; site-1 protease; subcutaneous; trafficking; transcription factor; tumor

The lymphatic vascular system is essential for transporting interstitial fluid, dietary fat, and immune cells. Defects  in these functions contribute to lymphedema, impaired lipid absorption, obesity, abnormal immune function, and  cancer metastasis. During embryonic development, lymphangiogenesis is robust, primarily driven by vascular  endothelial growth factor C (VEGF-­C)-­mediated activation of VEGFR-­3, a main VEGF-­C receptor on lymphatic  endothelial cells (LECs). Emerging evidence has shown the metabolism of endothelial cells is critical for vascular  development. Changes in EC metabolic pathways are found in pathologies such as cancer and diabetes as well. But  most research has been focused on blood endothelial metabolic pathways. Despite a few recent pioneering studies,  knowledge of LEC metabolism during lymphangiogenesis is limited. There is an unmet need to bridge the knowledge  gap between cellular metabolism and lymphatic vascular development. Site-­1 protease (S1P), encoded by  membrane-­bound transcription factor peptidase, site 1 (MBTPS1), is a serine protease in the Golgi apparatus. S1P is  a key regulator of cholesterol biosynthesis by proteolytic activation of a membrane-­bound latent transcription factor,  sterol-­regulatory element binding protein 2 (SREBP2). Recently, we found that mice with inducible endothelial cell-­ specific deficiency of S1P (iEC Mbtps1-­/-­, Mbtps1f/f;;Cdh5CreERT2) exhibited severe subcutaneous lymphedema and  defective lymphatic vasculature during development. Our pilot experiments also showed that mice with LEC-­specific  deficiency of SREBP2 (LEC Srebf2-­/-­, Srebf2f/f;;Lyve1Cre) had a similar lymphatic vascular defect during  development. These strong in vivo preliminary data support the central hypothesis that S1P/SREBP2-­mediated  cholesterol biosynthesis is required for lymphatic vascular development.  We will test the central hypothesis through two Aims: 1) determine whether lymphatic endothelial S1P/SREBP2-­ mediated cholesterol biosynthesis is required for lymphatic vascular development. We will characterize LEC cellular  defects, such as differentiation, migration, and proliferation, of S1P or SREBP2-­deficient mice at different stages of  embryonic development. These in vivo analyses will be complemented by in vitro assays using LECs isolated from  wild-­type (WT) or mutant mice as well as primary human LECs;; 2) determine mechanisms by which S1P/SREBP2-­ mediated cholesterol biosynthesis regulate lymphangiogenesis. Based on our preliminary results, we will primarily  test the hypothesis S1P/SREBP2-­mediated cholesterol biosynthesis is required for sustained VEGFR3 signaling  mainly by in vitro assays using WT or mutant LECs as well as human LECs with knockdown of S1P/SREBP2 or  functional inhibitors to S1P and SREBP2.  Based on strong preliminary data, our proposed study will reveal novel insights into roles of S1P-­mediated lipid  metabolism in lymphatic vascular development. Our study may lead to novel therapeutic opportunities for  pathologies with lymphatic vascular defects.

淋巴血管系统是运输间质液、膳食脂肪和免疫细胞所必需的。缺陷