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.
项目概要/摘要
该提案解决的挑战是生成一张地图,即全球人类细胞表面相互作用组,
定义了人类细胞表面蛋白 (CSP) 胞外域之间的体外相互作用,以及
分泌的蛋白质。这张图将对生物医学研究产生重大影响,因为细胞与细胞的相互作用
由 CSP 介导的细胞因子是人类生理学的核心,控制着几乎所有受影响的生物过程
通过疾病。 CSP 和分泌配体构成了已发现的大多数治疗靶点
近年来开发成功。了解互动伙伴对于评估互动伙伴至关重要
CSP 的治疗潜力,因为这种知识定义了它控制的生物过程。为了
例如,PD-1 于 1992 年被确定为 T 细胞功能的负调节因子,但其作为 T 细胞功能靶点的价值
癌症免疫疗法直到其配体 PD-L1 被鉴定并被发现是很久以后才变得清晰起来。
表达于肿瘤细胞上。我们不仅会生成人类之间体外相互作用的完整图谱
CSP 和分泌蛋白,还评估这些相互作用在人体免疫细胞中的功能
和神经系统。这是一个浩大的工程,因为人类的单次跨膜约有2000个
域 CSP 和 200 个“孤儿”分泌因子。创建所有这些之间的成对相互作用图
蛋白质需要测试 480 万次相互作用。这超出了现有筛选方法的能力,因此
在学术机构执行此屏幕需要开发新技术。这
项目太大,传统 RO1 无法支持,但非常适合变革性研究
奖励机制。在这里,我们提出了多重体外生化筛选和体内生化筛选的新方法
功能筛选,以便能够定义 CSP 和分泌的所有体外相互作用
配体并在 5 年资助期内评估其中许多配体的功能。为此,我们首先要
使用颜色编码的珠子和高亲和力纳米颗粒对体外相互作用组筛选进行多重分析和敏化。
然后我们将开发将体外蛋白质相互作用筛选转化为高通量 DNA 的方法
测序屏幕,具有巨大的多重能力。对于功能屏幕,复用单
细胞命运扰动的细胞分析可以让我们评估许多不同配体对单个细胞的影响
免疫系统和神经细胞在一次实验中。此处描述的总体方法的基本原理
是它定义了一个逐步的过程,在这个过程中我们系统地开发和优化屏幕技术,然后
使用最适合执行实际屏幕的技术。
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
- 批准号:
9143553 - 财政年份:2016
- 资助金额:
$ 270.14万 - 项目类别:
Novel Interferons and small molecule enhancers of the interferon pathway
新型干扰素和干扰素途径的小分子增强剂
- 批准号:
8643869 - 财政年份:2014
- 资助金额:
$ 270.14万 - 项目类别:
Engineering of macrophage phagocytosis for cancer and stem cell immunotherapy
用于癌症和干细胞免疫治疗的巨噬细胞吞噬工程
- 批准号:
8687302 - 财政年份:2014
- 资助金额:
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Engineering of macrophage phagocytosis for cancer and stem cell immunotherapy
用于癌症和干细胞免疫治疗的巨噬细胞吞噬工程
- 批准号:
8840913 - 财政年份:2014
- 资助金额:
$ 270.14万 - 项目类别:
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