Progenitor Cells for High Endothelium in the Immune Response
免疫反应中高内皮的祖细胞
基本信息
- 批准号:10592196
- 负责人:
- 金额:$ 63.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-25 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressApoptosisAtherosclerosisAtlasesAutoimmune DiseasesBiological AssayBloodBlood VesselsBlood capillariesCapillary Endothelial CellCell Fate ControlCell physiologyCellsChronicComplementCytometryDevelopmentDiseaseDown-RegulationEndoplasmic ReticulumEndothelial CellsEndotheliumFluorescenceGene ExpressionGene Expression ProfilingGene MutationGene TargetingGenerationsGenesGenetic TranscriptionGoalsGolgi ApparatusGrantGut associated lymphoid tissueHigh Endothelial VenuleHomeostasisHomingHumanImageImmuneImmune responseImmunityImmunizationImmunizeIn SituInflammationInflammatoryInformaticsKnowledgeLeukocytesLymphocyteLymphoid TissueMalignant NeoplasmsMetabolismMethodsMolecularMorphologyMusMyelogenousMyeloid CellsPathogenicityPathologicPathologyPathway interactionsPhenotypePhysiologicalProliferatingProteinsProteomicsRANK proteinRegulationRoleSecretory CellSignal TransductionSiteTestingTherapeuticTissuesTranscriptional RegulationTumor ImmunityUp-RegulationVaccinationVaccinesVenousXBP1 geneangiogenesisautoimmune inflammationcandidate identificationdraining lymph nodeendonucleaseendoplasmic reticulum stressgene functionhigh dimensionalityimmunoregulationinnovationinsightlymph nodesmigrationmolecular phenotypemouse modelnanoparticlenotch proteinnotch-2 proteinnovelnovel therapeutic interventionpostcapillary venuleprogenitorprogramsrecruitresponserole modelsegregationstem cell homeostasisstem cellstraffickingtumor
项目摘要
PROJECT SUMMARY
SUMMARY: High endothelial venules (HEV) are specialized portals for lymphocyte entry into lymphoid tissues
and sites of chronic inflammation from the blood. Along with flat walled postcapillary venules, they regulate
immune cell trafficking in physiologic and pathologic settings including autoimmune diseases, inflammation and
cancer. HEV in lymph nodes draining sites of immune challenge expand dramatically to support enhanced
lymphocyte recruitment, with new high endothelial cells (HEC) arising by proliferation and by neogenesis from
capillary resident progenitors (CRP). The molecular pathways that control HEV expansion and differentiation
from capillary precursors are as yet unclear; but generation of a comprehensive atlas of lymph node blood
endothelial cell subsets, molecular phenotypes and responses to immune challenge now allows us to identify
candidate pathways involved. Our fundamental focus in this renewal application is therefore to identify and
characterize novel mechanisms of HEV specialization and generation in the immune response. In this context
we will mechanistically define pathways that i) regulate progenitor cell homeostasis and transitional EC
expansion in immune angiogenesis; ii) induce the unique "high" endothelial morphology and metabolism of
HEV, regulating "HEVness" and function; and iii) control the cell-fate decision that directs transitional EC
towards lymphocyte-recruiting HEV (vs non-HEV PCV) differentiation. We will apply innovative approaches to
address these fundamental gaps in knowledge including scRNAseq and mass proteomic EC profiling, novel
pan-EC and CRP-specific gene-targeted mice, and nanoparticle methods to manipulate EC-subset specific
gene expression. Elucidation of the mechanisms of endothelial cell specialization and homeostasis in lymphoid
tissues, including mechanisms regulating endothelial cells that control lymphocyte homing, will lead to novel
targets and approaches for the control of autoimmune inflammation and for therapeutic regulation of immune
cell traffic for vaccination and cancer immunity.
项目总结
摘要:高内皮微静脉(HEV)是淋巴细胞进入淋巴组织的特殊通道。
以及血液中的慢性炎症部位。它们与扁平的毛细血管后小静脉一起调节
生理和病理环境中的免疫细胞运输,包括自身免疫性疾病、炎症和
癌症。HEV在淋巴引流部位的免疫挑战急剧扩大,以支持增强
淋巴细胞募集,由于增殖和新生而产生新的高内皮细胞(HEC)
毛细血管常驻祖细胞(CRP)。控制HEV扩增和分化的分子途径
来自毛细血管的前体尚不清楚;但生成一份全面的淋巴结血图谱
内皮细胞亚群、分子表型和对免疫挑战的反应现在使我们能够识别
涉及的候选路径。因此,我们在此次续签申请中的基本重点是识别和
描述免疫应答中HEV特化和生成的新机制。在此背景下
我们将从机制上定义如下途径:1)调节祖细胞动态平衡和过渡性EC
免疫血管生成的扩张;ii)诱导血管内皮细胞独特的高形态和代谢
HEV,规范“HEV”和功能;以及III)控制指导过渡EC的细胞命运决定
向淋巴细胞募集型HEV(与非HEV PCV)分化。我们将创新方式应用于
解决包括scRNAseq和大量蛋白质组EC图谱在内的知识中的这些根本差距,新颖
PAN-EC和CRP-特异性基因靶向小鼠,以及操纵EC-亚集特异性的纳米颗粒方法
基因表达。淋巴组织内皮细胞特化和动态平衡机制的阐明
组织,包括调控内皮细胞控制淋巴细胞归巢的机制,将导致新的
自身免疫性炎症控制和免疫治疗调节的靶点和途径
用于疫苗接种和癌症免疫的细胞流量。
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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{{ truncateString('EUGENE C BUTCHER', 18)}}的其他基金
Tumor and Immune Programming of Tumor-AssociatedEndothelium
肿瘤和肿瘤相关内皮细胞的免疫编程
- 批准号:
10532149 - 财政年份:2018
- 资助金额:
$ 63.81万 - 项目类别:
Tumor and Immune Programming of Tumor-AssociatedEndothelium
肿瘤和肿瘤相关内皮细胞的免疫编程
- 批准号:
10303033 - 财政年份:2018
- 资助金额:
$ 63.81万 - 项目类别:
Tumor and Immune Programming of Tumor-Associated Endothelium
肿瘤和肿瘤相关内皮细胞的免疫编程
- 批准号:
10054980 - 财政年份:2018
- 资助金额:
$ 63.81万 - 项目类别:
Progenitor Cells for High Endothelium in the Immune Response
免疫反应中高内皮的祖细胞
- 批准号:
9755349 - 财政年份:2017
- 资助金额:
$ 63.81万 - 项目类别:
Progenitor Cells for High Endothelium in the Immune Response
免疫反应中高内皮的祖细胞
- 批准号:
10223152 - 财政年份:2017
- 资助金额:
$ 63.81万 - 项目类别:
Transcriptional Profiling of Human High Endothelial Venules
人类高内皮小静脉的转录谱
- 批准号:
9212639 - 财政年份:2016
- 资助金额:
$ 63.81万 - 项目类别:
Chemerin in Tumor Immunity and Surveillance
Chemerin 在肿瘤免疫和监测中的作用
- 批准号:
9041803 - 财政年份:2015
- 资助金额:
$ 63.81万 - 项目类别:
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