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
基本信息
- 批准号:10400114
- 负责人:
- 金额:$ 43.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAnabolismApoptosisBloodBlood VesselsCardinal veinCell membraneCellsCellular Metabolic ProcessCholesterolCholesterol HomeostasisComplementDataDefectDevelopmentDiabetes MellitusDietary FatsDorsalEmbryonic DevelopmentEndothelial CellsEndotheliumExhibitsFeedbackGenesGenetic TranscriptionGlutamineGlycolysisGolgi ApparatusHumanImmuneImpairmentInfectionInflammationIntercellular FluidKDR geneKnowledgeLeadLipidsLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic EndotheliumLymphedemaMalignant NeoplasmsMediatingMembraneMetabolic PathwayMetabolismModelingMusMutant Strains MiceNamesNeoplasm MetastasisObesityOperative Surgical ProceduresPathologyPeptide HydrolasesPhenotypePhysiologicalPrimary Lymph SacProcessProliferatingReportingResearchRoleSRE-2 binding proteinSerine ProteaseSignal TransductionSiteSkinStructureTestingVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3Vascular SystemWild Type Mouseabsorptionbasecell growthcholesterol biosynthesisdriving forceearly embryonic stageexperimental studyfatty acid oxidationimmune functionin vitro Assayin vivoinhibitorinsightknock-downlipid metabolismlymphatic developmentlymphatic vasculaturelymphatic vesselmigrationmouse developmentmutantnovelnovel therapeuticsrapid growthreceptorsite-1 proteasesubcutaneoustraffickingtranscription factortumor
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lijun Xia其他文献
Lijun Xia的其他文献
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{{ truncateString('Lijun Xia', 18)}}的其他基金
Center for Cellular Metabolism Research in Oklahoma
俄克拉荷马州细胞代谢研究中心
- 批准号:
10797920 - 财政年份:2021
- 资助金额:
$ 43.7万 - 项目类别:
Center for Cellular Metabolism Research in Oklahoma
俄克拉荷马州细胞代谢研究中心
- 批准号:
10399960 - 财政年份:2021
- 资助金额:
$ 43.7万 - 项目类别:
Center for Cellular Metabolism Research in Oklahoma
俄克拉荷马州细胞代谢研究中心
- 批准号:
10853688 - 财政年份:2021
- 资助金额:
$ 43.7万 - 项目类别:
Center for Cellular Metabolism Research in Oklahoma
俄克拉荷马州细胞代谢研究中心
- 批准号:
10571889 - 财政年份:2021
- 资助金额:
$ 43.7万 - 项目类别:
Center for Cellular Metabolism Research in Oklahoma
俄克拉荷马州细胞代谢研究中心
- 批准号:
10339346 - 财政年份:2021
- 资助金额:
$ 43.7万 - 项目类别:
Center for Cellular Metabolism Research in Oklahoma
俄克拉荷马州细胞代谢研究中心
- 批准号:
10090975 - 财政年份:2021
- 资助金额:
$ 43.7万 - 项目类别:
Site-1 protease-mediated lipid metabolism in lymphatic vascular development
位点 1 蛋白酶介导的淋巴管发育中的脂质代谢
- 批准号:
10629188 - 财政年份:2020
- 资助金额:
$ 43.7万 - 项目类别:
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