Investigating the interplay of structural, molecular and spatial mechanisms that control SHP2 activity downstream of PD1

研究控制 PD1 下游 SHP2 活性的结构、分子和空间机制的相互作用

基本信息

  • 批准号:
    10002277
  • 负责人:
  • 金额:
    $ 34.63万
  • 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:
    2018-09-01 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT The immune system's ability to adjust the potency of its response to an external threat is exploited by most immunotherapies. Targeting the inhibitory receptors PD1 or CTLA4 to modulate the activity and function of T cells has been an extremely successful strategy for treating cancer. These checkpoint therapies block the extracellular domains of cell surface receptors with antibodies. However, antibodies often have inadequate pharmacokinetics and cannot penetrate relevant tissues. Alternative ways of inhibiting these trans-membrane receptors by targeting downstream effectors are currently not available, as the molecular mechanisms of signal transduction are not fully understood, and the identified intracellular signaling molecules are important in a wide range of cell types, signaling pathways, and cellular compartments. Thus, it is important to characterize signal transduction mechanisms that are specific to T cells. The recruitment and activation of downstream kinases and phosphatases by transmembrane receptors is one way that this specificity is achieved. This study investigates the mechanism by which the SHP2 phosphatase is recruited to and activated by the inhibitory receptor PD1 in T cells. To this end, a multidisciplinary approach will be employed that utilizes biochemical, structural, and biophysical approaches, as well as single molecule imaging, namely super resolution fluorescence microscopy and single particle tracking. First, the effects of SHP2 phosphorylation and PD1 binding on SHP2 conformation and phosphatase activity will be examined. Hydrogen-Deuterium Exchange – Mass spectrometry analyses of wild-type and mutant versions of SHP2 (in their phosphorylated and/or PD1 bound forms) will determine the nature and locations of conformational changes in SHP2. This information will be correlated to changes in activity to identify structure-function relationships. Second, interaction dynamics between SHP2 and PD1 will be analyzed in vivo and in vitro. Microscopy approaches will be used to determine recruitment kinetics of SHP2 to PD1 and correlate them to changes in SHP2 binding affinities. Mutant analyses will explore the molecular underpinning of these interactions and determine whether they can be altered to modulate T cell responses, as well as affect disease onset and progression in mouse models of melanoma and diabetes. Third, the spatio-temporal relations between SHP2, PD1, and components of the T cell receptor signaling pathway will be investigated using cutting edge single molecule imaging technologies. These approaches will also utilize wild-type and mutant versions of SHP2 to determine whether the membrane dynamics and distribution of SHP2 can be altered to change T cell immune responses. In conclusion, the suggested research will uncover mechanisms unique to the activation of SHP2 through the PD1 pathway in activated T cells. These mechanisms are potential targets for allosteric and small molecule inhibitors, thereby providing a viable alternative to current immunotherapies.
摘要

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)
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Ye Zheng其他文献

Ye Zheng的其他文献

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{{ truncateString('Ye Zheng', 18)}}的其他基金

Define the role of REV-ERB in colonic RORgt+ regulatory T cells
定义 REV-ERB 在结肠 RORgt 调节性 T 细胞中的作用
  • 批准号:
    10753360
  • 财政年份:
    2023
  • 资助金额:
    $ 34.63万
  • 项目类别:
A novel role of hypusination in controlling regulatory T cell function
hypusination 在控制调节性 T 细胞功能中的新作用
  • 批准号:
    10356173
  • 财政年份:
    2021
  • 资助金额:
    $ 34.63万
  • 项目类别:
Treg development and function controlled by cis-regulatory circuits
由顺式调节电路控制的 Treg 发育和功能
  • 批准号:
    10318638
  • 财政年份:
    2014
  • 资助金额:
    $ 34.63万
  • 项目类别:
Regulatory T cell lineage stability controlled by Foxp3 CNS2
Foxp3 CNS2 控制的调节性 T 细胞谱系稳定性
  • 批准号:
    9197261
  • 财政年份:
    2014
  • 资助金额:
    $ 34.63万
  • 项目类别:
Treg development and function controlled by cis-regulatory circuits
由顺式调节电路控制的 Treg 发育和功能
  • 批准号:
    10092894
  • 财政年份:
    2014
  • 资助金额:
    $ 34.63万
  • 项目类别:
Mechanisms controlling Foxp3 expression and regulatory T cell homeostasis
控制 Foxp3 表达和调节性 T 细胞稳态的机制
  • 批准号:
    8658598
  • 财政年份:
    2013
  • 资助金额:
    $ 34.63万
  • 项目类别:
Shared Resource-Flow Cytometry Core
共享资源-流式细胞术核心
  • 批准号:
    10328943
  • 财政年份:
    1996
  • 资助金额:
    $ 34.63万
  • 项目类别:
Shared Resource-Flow Cytometry Core
共享资源-流式细胞术核心
  • 批准号:
    10114238
  • 财政年份:
    1996
  • 资助金额:
    $ 34.63万
  • 项目类别:
Shared Resource-Flow Cytometry Core
共享资源-流式细胞术核心
  • 批准号:
    10560570
  • 财政年份:
    1996
  • 资助金额:
    $ 34.63万
  • 项目类别:

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