A Global Map of Interactions Among Human Cell Surface Proteins and Secreted Ligands
人类细胞表面蛋白和分泌配体之间相互作用的全局图
基本信息
- 批准号:10710033
- 负责人:
- 金额:$ 270.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-30 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAffectAffinity ChromatographyAvidityAwardBindingBiochemicalBiological AssayBiological ProcessBiomedical ResearchCell CommunicationCell Surface ProteinsCell physiologyCell surfaceCellsCellular AssayChimeric ProteinsCodeColorCommunitiesDevelopmentDiseaseEnzyme-Linked Immunosorbent AssayEvaluationExtracellular DomainFundingGene ExpressionGenesGoalsHigh-Throughput DNA SequencingHumanImmune systemImmunotherapyIn VitroInstitutionKnowledgeLigandsMapsMass Spectrum AnalysisMediatingMethodsNervous SystemNeuronsOrphanPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhysiologyProcessProtein SecretionProteinsResearchResourcesT-LymphocyteTechnologyTestingTherapeuticTransmembrane DomainYeastsanti-tumor immune responsecancer immunotherapyexperimental studyin vitro Assayin vivoinnovationinsightknock-downnanoparticleneoplastic cellnerve stem cellneuralnew technologynew therapeutic targetnovel therapeuticsorgan growthprogrammed cell death ligand 1programmed cell death protein 1screeningsingle cell analysissingle cell mRNA sequencingtherapeutic targetyeast two hybrid system
项目摘要
PROJECT SUMMARY/ABSTRACT
The challenge addressed by this proposal is to generate a map, the global human cell-surface interactome,
that defines in vitro interactions among the extracellular domains of human cellsurface proteins (CSPs) and
secreted proteins. This map will have a major impact on biomedical research, because cell-cell interactions
mediated by CSPs are central to human physiology, controlling almost every biological process that is affected
by disease. CSPs and secreted ligands comprise the majority of the therapeutic targets that have been
successfully developed in recent years. Knowledge of interaction partners is essential for assessing the
therapeutic potential of a CSP, since this knowledge defines the biological processes that it controls. For
example, PD-1 was identified as a negative regulator of T cell function in 1992, but its value as a target for
cancer immunotherapy only became clear much later, when its ligand PD-L1 was identified and found to be
expressed on tumor cells. We will not only generate a complete map of in vitro interactions among human
CSPs and secreted proteins, but also assess the functions of these interactions in cells of the human immune
and nervous systems. This is a huge project, because there are about 2000 human single-transmembrane
domain CSPs and 200 “orphan” secreted factors. Creation of a map of pairwise interactions among all of these
proteins requires testing 4.8 million interactions. This is beyond the capacity of current screening methods, so
execution of this screen at an academic institution will require the development of new technologies. This
project is too large to be supported by a traditional RO1, but is perfectly suited to the transformative research
award mechanism. Here we propose new ways to multiplex both in vitro biochemical screens and in vivo
functional screens, so as to make it possible to define all in vitro interactions among CSPs and secreted
ligands and to assess the functions of many of these within a 5-year funding period. To do this, we will first
multiplex and sensitize in vitro interactome screens using color-coded beads and high-avidity nanoparticles.
We will then develop methods to convert in vitro protein interaction screens into high-throughput DNA
sequencing screens, which have a huge multiplexing capacity. For the functional screens, multiplexing single-
cell analysis of cell fate perturbations can allow us to assess the effects of many different ligands on single
immune system and neural cells in a single experiment. The rationale for the overall approach described here
is that it defines a stepwise process in which we systematically develop and optimize screen technologies, then
use the technology that performs best for execution of the actual screens.
项目总结/文摘
项目成果
期刊论文数量(2)
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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Kenan Christopher GARCIA其他文献
Kenan Christopher GARCIA的其他文献
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{{ truncateString('Kenan Christopher GARCIA', 18)}}的其他基金
A Global Map of Interactions Among Human Cell Surface Proteins and Secreted Ligands
人类细胞表面蛋白和分泌配体之间相互作用的全局图
- 批准号:
10478763 - 财政年份:2022
- 资助金额:
$ 270.14万 - 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
- 批准号:
10176894 - 财政年份:2018
- 资助金额:
$ 270.14万 - 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
- 批准号:
9761520 - 财政年份:2018
- 资助金额:
$ 270.14万 - 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
- 批准号:
10197113 - 财政年份:2018
- 资助金额:
$ 270.14万 - 项目类别:
Structure-based Bioengineering of Wnt Surrogates for Intestinal Stem Cell Biology and Therapy
用于肠干细胞生物学和治疗的 Wnt 替代物的基于结构的生物工程
- 批准号:
10447202 - 财政年份:2018
- 资助金额:
$ 270.14万 - 项目类别:
Viral GPCR recognition of chemokines and engineered ligands
病毒 GPCR 识别趋化因子和工程配体
- 批准号:
9298587 - 财政年份:2016
- 资助金额:
$ 270.14万 - 项目类别:
Viral GPCR recognition of chemokines and engineered ligands
病毒 GPCR 识别趋化因子和工程配体
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9143553 - 财政年份:2016
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Novel Interferons and small molecule enhancers of the interferon pathway
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- 资助金额:
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Engineering of macrophage phagocytosis for cancer and stem cell immunotherapy
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8840913 - 财政年份:2014
- 资助金额:
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