Deconvoluting the Vascular Adhesome
去卷积血管粘附体
基本信息
- 批准号:10327637
- 负责人:
- 金额:$ 78.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdhesionsBinding SitesBiochemicalBloodBlood PlateletsBlood VesselsCell AdhesionCell LineCellsComplexDataEndothelial CellsFamilyFoundationsFutureHealth behaviorHeterogeneityImageIntegrin alpha ChainsIntegrin beta ChainsIntegrinsLeukocytesLigationMesenchymalMethodsMolecularMyocardial InfarctionOutputProcessProteinsRegulationResourcesRodSignal TransductionSiteStrokeStructureTalinTestingVinculinbasecell motilitydensitydynamical evolutionexperimental studymembernovel strategiesphysical statetherapeutic target
项目摘要
Summary
Integrin-based adhesions are central to the functions of blood and vascular cells. The
heterogeneity of adhesions and their dynamic evolution has complicated efforts to study their fine
composition, assembly, and disassembly. Our studies have shown that a transition between two
adhesion archetypes is controlled by a simple binary molecular switch of vinculin competition with
and displacement of RIAM or lamellipodin(Lpd), members of the MRL family, from binding sites
on talin's rod domain. Furthermore, we developed methods to image the complex of MRL proteins
with integrins and talin (MIT complex) and showed that it formed the tips of “sticky fingers,” cellular
protrusions that sense the density of matrix proteins and physical state of the substrate during
mesenchymal cell migration. mesenchymal cell migration. We hypothesize that the MIT
complex represents one among many distinct modules that contribute to the overall
structure and function of integrin- based adhesions. This suggests the paradigm that the
integrin adhesome can be analyzed as a dynamic assembly of these modules, which form prior to
entry into the adhesions. This concept has enabled us to propose a new approach to studying
adhesions by developing methods to purify each module formed prior to integrin ligation. To test
this paradigm, we propose to purify 4 such modules and to characterize each for a) the presence
of talin-activated integrins b) characterize its protein composition. c) establish its biochemical
topology and regulation d) visualize it in living cells and e) evaluate its functions The proposed
experiments will generate foundational data for the adhesion field in three ways: a) the integrin
adhesome will be re- interpreted as a compendium of modular components; each with its own
specific composition. b) The functional studies will identify new regulators of blood and vascular
cell adhesion and signaling that may be exploitable as therapeutic targets c) A complete definition
of the protein composition of each module will serve as a public resource for the analysis of
integrin-based adhesions and will be hypothesis-generating for future studies to understand the
regulation of assembly of each module and its functional outputs.
总结
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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Mark HOWARD Ginsberg其他文献
Mark HOWARD Ginsberg的其他文献
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{{ truncateString('Mark HOWARD Ginsberg', 18)}}的其他基金
Cellular Mechanisms of Inflammation, Hemostasis, and Thrombosis
炎症、止血和血栓形成的细胞机制
- 批准号:
10229365 - 财政年份:2020
- 资助金额:
$ 78.7万 - 项目类别:
Cellular Mechanisms of Inflammation, Hemostasis, and Thrombosis
炎症、止血和血栓形成的细胞机制
- 批准号:
10676869 - 财政年份:2020
- 资助金额:
$ 78.7万 - 项目类别:
Direct Rap1-talin interaction in platelets, leukocytes, and endothelial cells
Rap1-talin 在血小板、白细胞和内皮细胞中的直接相互作用
- 批准号:
10229368 - 财政年份:2020
- 资助金额:
$ 78.7万 - 项目类别:
Direct Rap1-talin interaction in platelets, leukocytes, and endothelial cells
Rap1-talin 在血小板、白细胞和内皮细胞中的直接相互作用
- 批准号:
10676892 - 财政年份:2020
- 资助金额:
$ 78.7万 - 项目类别:
Anti-Coagulant and Cytoprotective activity in CCM pathogenesis
CCM 发病机制中的抗凝血和细胞保护活性
- 批准号:
10417155 - 财政年份:2015
- 资助金额:
$ 78.7万 - 项目类别:
Anti-Coagulant and Cytoprotective activity in CCM pathogenesis
CCM 发病机制中的抗凝血和细胞保护活性
- 批准号:
10621253 - 财政年份:2015
- 资助金额:
$ 78.7万 - 项目类别:
Anti-Coagulant and Cytoprotective activity in CCM pathogenesis
CCM 发病机制中的抗凝血和细胞保护活性
- 批准号:
10220146 - 财政年份:2015
- 资助金额:
$ 78.7万 - 项目类别:
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