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
- 来源:
- 关键词:AffectAffinityAnimal Disease ModelsAntibodiesAntibody TherapyArchitectureAreaAutoimmunityBindingBiochemicalBiophysicsBlocking AntibodiesCD28 geneCTLA4 geneCell Surface ReceptorsCell membraneCell physiologyComplexDataDefectDeuteriumDevelopmentDiabetes MellitusDiabetic mouseDiseaseDisease ProgressionDrug KineticsEnsureExtracellular DomainFluorescence MicroscopyGoalsHydrogenImaging TechniquesImaging technologyImmune responseImmune systemImmunomodulatorsImmunotherapyIn VitroInfectionKineticsLocationMalignant NeoplasmsMass Spectrum AnalysisMembraneMicroscopyMolecularMolecular ConformationMovementMultiprotein ComplexesNatureOnset of illnessPD-1 pathwayPTPN11 genePathway interactionsPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhosphotyrosinePlant RootsPost-Translational Protein ProcessingProcessResearchResolutionSignal PathwaySignal TransductionSignaling MoleculeSpecificityStructureStructure-Activity RelationshipT Cell Receptor Signaling PathwayT cell responseT-LymphocyteTestingTimeTissuesZAP-70 Geneanti-CTLA-4 therapyanti-PD1 antibodiesassaultbasebiophysical techniquescancer immunotherapycell typecheckpoint therapyenzyme activityin vivoinnovationinorganic phosphateinsightinterdisciplinary approachmelanomamolecular imagingmouse modelmutantnovelnovel drug classnovel therapeutic interventionparticleprogrammed cell death protein 1receptorrecruitresponsesingle moleculesmall molecule inhibitorspatial relationshipspatiotemporalsrc Homology Region 2 Domaintargeted treatment
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)
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