Molecular and functional investigation of the role of CD1 in gamma delta T cell surveillance

CD1 在 γ δ T 细胞监测中作用的分子和功能研究

基本信息

  • 批准号:
    10268214
  • 负责人:
  • 金额:
    $ 52.47万
  • 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:
    2020-09-22 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

γδ T cells constitute an important component of the immune response against infectious agents and cancerous transformations, yet the biochemical mechanisms by which they detect antigen through their somatically recombined T cell receptor (TCR) remain unclear. Unlike αβTCRs, which are restricted to recognizing antigens in the context of Major Histocompatibility Complex (MHC) molecules, γδTCRs can recognize a diversity of ligands ranging from self MHC to intact, unprocessed, viral glycoproteins. Our recent work has established CD1 molecules as ligands for a subpopulation of human Vδ1 γδ T cells, producing robust functional, biochemical and structural evidence. We seek to extend our studies to the human gut, where γδ T cells, and in particular, Vδ1+ T cells, predominate. Our preliminary data suggests that CD1 recognition is robust and present in all individuals examined, and that there exist important functional differences between CD1 reactive γδ T cells in tumors versus healthy adjoining tissue. Thus, the long-term goal of this proposal is to fully characterize this CD1 reactive population in tumors versus healthy tissue, examining their functional effector phenotypes, TCR repertoire and immunomodulatory signals, in addition to the TCR, that shape the recruitment, activation and potential expansion of these cells in the context of a highly relevant human disease, colorectal cancer. Our first aim, “Characterization of CD1-specific γδ T cells in normal and diseased tissue.”, seeks to use classical cellular expansions complemented by direct ex vivo functional and transcript analysis to profile CD1 reactive and non- reactive T cell populations derived from tumor and adjoining healthy tissue. These data will provide insight into the signals that regulate γδ T cells within the tumor microenvironment compared to healthy tissue. Our second aim, “Elucidation of the molecular mechanisms by which γδ TCRs bind to CD1/lipid complexes.”, will focus on characterizing the interaction between the γδ TCRs expressed by these cells and CD1/lipid antigen. We will use protein biochemistry, biophysics and x-ray crystallography to elucide the molecular mechanisms by which the γδ TCR recognizes CD1/lipid. Our effort will significantly expand our understanding of the specific signals that regulate γδ T cell activity in human health and disease. Our third aim, “Determine the presence and role of ligand, co-stimulatory and/or co-receptor molecules in CD1 specific γδ T cell activation and phenotype in the colon” will characterize the ligand and immunomodulatory signals that may regulate the activity of CD1 reactive γδ T cells in the context of human colorectal cancer. We will combine RNAseq and differentiation assays using cord blood derived, naïve Vδ1 cells to test the relevance of candidate signals. This will be complemented by in vitro derived native Vδ1 T cells through the OP9/DL1 system. γδ T cells can be either pro-inflammatory or regulatory, therefore we seek to understand which role these cells play, if any, in this disease state. Together, these aims will begin to unravel the mystery of γδ T cells in human immunobiology, both at the cellular and molecular levels.
γδ T细胞构成针对感染因子和癌性免疫应答的重要组分。 转化,但生化机制,他们检测抗原通过其体细胞 重组T细胞受体(TCR)的作用尚不清楚。与αβ TCR不同,α β TCR仅限于识别抗原 在主要组织相容性复合物(MHC)分子的背景下,γδ TCR可以识别多种配体, 从自身MHC到完整的、未加工的病毒糖蛋白。我们最近的工作建立了CD 1 分子作为人Vδ1 γδ T细胞亚群的配体,产生强大的功能性、生物化学和生物学特性。 结构性证据。我们试图将我们的研究扩展到人类肠道,在那里γδ T细胞,特别是Vδ1+, T细胞占优势。我们的初步数据表明,CD 1识别是强大的,并存在于所有个人 研究表明,肿瘤中的CD 1反应性γδ T细胞与 健康的邻近组织。因此,该提案的长期目标是充分表征这种CD 1反应性的细胞因子。 在肿瘤与健康组织中,检测其功能性效应子表型、TCR库和 免疫调节信号,除了TCR,形成募集,激活和潜在的扩张 这些细胞与一种高度相关的人类疾病结直肠癌的关系。我们的第一个目标, “Characterization of CD1-specific γδ T cells in normal and diseased tissue.",试图利用经典的细胞 通过直接离体功能和转录分析补充扩增,以分析CD 1反应性和非反应性 来源于肿瘤和邻近健康组织的反应性T细胞群。这些数据将提供洞察力, 与健康组织相比,肿瘤微环境中调节γδ T细胞的信号。我们的第二 目的,“阐明γδ TCR与CD 1/脂质复合物结合的分子机制",将 重点在于表征这些细胞表达的γδ TCR与CD 1/脂质抗原之间的相互作用。 我们将使用蛋白质生物化学、生物物理学和x射线晶体学来阐明分子机制, 其中γδ TCR识别CD 1/脂质。我们的努力将大大扩大我们对具体的 在人类健康和疾病中调节γδ T细胞活性的信号。我们的第三个目标,“确定 以及配体、共刺激和/或共受体分子在CD 1特异性γδ T细胞活化中的作用, “结肠中的表型”将表征可以调节结肠的配体和免疫调节信号。 人结直肠癌中CD 1反应性γδ T细胞的活性。我们将联合收割机RNAseq和 使用脐带血来源的幼稚Vδ1细胞进行分化测定以测试候选信号的相关性。这 将通过0 P9/DL 1系统由体外衍生的天然VSlT细胞补充。γδ T细胞可以是 促炎或调节,因此我们试图了解这些细胞在这种疾病中发挥的作用,如果有的话, 状态总之,这些目标将开始揭开γδ T细胞在人类免疫生物学中的神秘面纱,无论是在 细胞和分子水平。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Erin June Adams其他文献

Erin June Adams的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Erin June Adams', 18)}}的其他基金

Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines
多发性骨髓瘤细胞系中非经典 MHC 相关蛋白 MR1 内源配体库的研究
  • 批准号:
    10557884
  • 财政年份:
    2022
  • 资助金额:
    $ 52.47万
  • 项目类别:
Molecular and functional investigation of the role of HLA-F in immune regulation
HLA-F在免疫调节中作用的分子和功能研究
  • 批准号:
    10503676
  • 财政年份:
    2022
  • 资助金额:
    $ 52.47万
  • 项目类别:
Molecular and functional investigation of the role of HLA-F in immune regulation
HLA-F在免疫调节中作用的分子和功能研究
  • 批准号:
    10636894
  • 财政年份:
    2022
  • 资助金额:
    $ 52.47万
  • 项目类别:
Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines
多发性骨髓瘤细胞系中非经典 MHC 相关蛋白 MR1 内源配体库的研究
  • 批准号:
    10452305
  • 财政年份:
    2022
  • 资助金额:
    $ 52.47万
  • 项目类别:
Determining the Origins of Nonclassical Class I molecules through Molecular and Functional Approaches
通过分子和功能方法确定非经典 I 类分子的起源
  • 批准号:
    10501472
  • 财政年份:
    2022
  • 资助金额:
    $ 52.47万
  • 项目类别:
Determining the Origins of Nonclassical Class I molecules through Molecular and Functional Approaches
通过分子和功能方法确定非经典 I 类分子的起源
  • 批准号:
    10645114
  • 财政年份:
    2022
  • 资助金额:
    $ 52.47万
  • 项目类别:
Facility and Building System Upgrades Support for the Howard T. Ricketts Biocontainment Laboratory
为 Howard T. Ricketts 生物防护实验室提供设施和建筑系统升级支持
  • 批准号:
    10394614
  • 财政年份:
    2021
  • 资助金额:
    $ 52.47万
  • 项目类别:
Facility and Building System Upgrades Support for the Howard T. Ricketts Biocontainment Laboratory
为 Howard T. Ricketts 生物防护实验室提供设施和建筑系统升级支持
  • 批准号:
    10631368
  • 财政年份:
    2021
  • 资助金额:
    $ 52.47万
  • 项目类别:
Molecular and functional investigation of the role of CD1 in gamma delta T cell surveillance
CD1 在 γ δ T 细胞监测中作用的分子和功能研究
  • 批准号:
    10670830
  • 财政年份:
    2020
  • 资助金额:
    $ 52.47万
  • 项目类别:
Molecular and functional investigation of the role of CD1 in gamma delta T cell surveillance
CD1 在 γ δ T 细胞监测中作用的分子和功能研究
  • 批准号:
    10462661
  • 财政年份:
    2020
  • 资助金额:
    $ 52.47万
  • 项目类别:

相似海外基金

Investigating the Adoption, Actual Usage, and Outcomes of Enterprise Collaboration Systems in Remote Work Settings.
调查远程工作环境中企业协作系统的采用、实际使用和结果。
  • 批准号:
    24K16436
  • 财政年份:
    2024
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
WELL-CALF: optimising accuracy for commercial adoption
WELL-CALF:优化商业采用的准确性
  • 批准号:
    10093543
  • 财政年份:
    2024
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Collaborative R&D
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
  • 批准号:
    24K16488
  • 财政年份:
    2024
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 52.47万
  • 项目类别:
    EU-Funded
Assessing the Coordination of Electric Vehicle Adoption on Urban Energy Transition: A Geospatial Machine Learning Framework
评估电动汽车采用对城市能源转型的协调:地理空间机器学习框架
  • 批准号:
    24K20973
  • 财政年份:
    2024
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 52.47万
  • 项目类别:
    EU-Funded
De-Adoption Beta-Blockers in patients with stable ischemic heart disease without REduced LV ejection fraction, ongoing Ischemia, or Arrhythmias: a randomized Trial with blinded Endpoints (ABbreviate)
在没有左心室射血分数降低、持续性缺血或心律失常的稳定型缺血性心脏病患者中停用β受体阻滞剂:一项盲法终点随机试验(ABbreviate)
  • 批准号:
    481560
  • 财政年份:
    2023
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Operating Grants
Our focus for this project is accelerating the development and adoption of resource efficient solutions like fashion rental through technological advancement, addressing longer in use and reuse
我们该项目的重点是通过技术进步加快时装租赁等资源高效解决方案的开发和采用,解决更长的使用和重复使用问题
  • 批准号:
    10075502
  • 财政年份:
    2023
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Grant for R&D
Engage2innovate – Enhancing security solution design, adoption and impact through effective engagement and social innovation (E2i)
Engage2innovate — 通过有效参与和社会创新增强安全解决方案的设计、采用和影响 (E2i)
  • 批准号:
    10089082
  • 财政年份:
    2023
  • 资助金额:
    $ 52.47万
  • 项目类别:
    EU-Funded
Collaborative Research: SCIPE: CyberInfrastructure Professionals InnoVating and brOadening the adoption of advanced Technologies (CI PIVOT)
合作研究:SCIPE:网络基础设施专业人员创新和扩大先进技术的采用 (CI PIVOT)
  • 批准号:
    2321091
  • 财政年份:
    2023
  • 资助金额:
    $ 52.47万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了