Synthetic biology toolkit for precise tuning of T cell activity
用于精确调节 T 细胞活性的合成生物学工具包
基本信息
- 批准号:10751879
- 负责人:
- 金额:$ 22.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-10 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAntigensBindingBiomedical ResearchC-terminalCAR T cell therapyCD19 geneCaffeineCalcineurinCalciumCalcium ChannelCalcium Channel BlockersCell TherapyCell membraneCell physiologyCellular immunotherapyChemicalsCoupledCytoplasmic GranulesCytosolDataDimerizationDiseaseDistalEndoplasmic ReticulumEngineeringEnzymesEventExhibitsFDA approvedFaceFunctional disorderGeneticGenetic TranscriptionGoalsHandHematologic NeoplasmsHyperactivityImmunotherapyIn VitroInflammatoryIntelligenceInterventionIon ChannelKineticsLightLymphocyte ActivationMalignant NeoplasmsModelingModificationMolecularMolecular ConformationNamesNuclear TranslocationPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhysiological ProcessesPilot ProjectsProcessProductionProtein DephosphorylationProteinsPublicationsReceptor SignalingRouteSTIM1 geneSafetySchemeSeriesSignal TransductionSystemT cell therapyT-Cell ActivationT-Cell Activation PathwayT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsTailTestingTherapeuticTimeToxic effectadaptive immunityanergycalmodulin-dependent protein kinase IIcell mediated immune responsechimeric antigen receptorchimeric antigen receptor T cellscytokinecytokine release syndromedesignexhaustionhuman diseaseimmunoengineeringimprovedin vivoinnovationneurotoxicitynovelnuclear factors of activated T-cellsoptogeneticspublic health relevancerecruitside effectsmall molecule inhibitorsynthetic biologytooltranscription factortranslational potential
项目摘要
Project Summary / Abstract. Chimeric antigen receptor (CAR) T cell-based immunotherapy has
shown curative potential in patients with haematological malignancies. However, it faces significant safety issues
(e.g., cytokine release syndrome and neurotoxicity) and efficacy loss arising from tonic signaling and T cell
exhaustion. These undesireable features are more or less decoded in the distal end of lymphocyte activation
pathway, the two-component Calcium Release-Activated Calcium (CRAC) channel composed of stromal
interaction molecule (STIM) and ORAI to form a major Ca2+ entry route in T cells and control T cell activation.
Upon T-cell receptor (TCR) engagement, Ca2+ depletion in the endoplasmic reticulum (ER) is sensed by stromal
interaction molecule 1 (STIM1) to initiate a series of conformational changes, culminating in the activation of the
pore-forming subunit of the CRAC channel, ORAI1. Ca2+ influx induces a series of processes in T cells, including
the secretion of cytolytic granules and the activation of Ca2+-dependent enzymes, including calcineurin, CaMKII
and Erk1/2, as well as master transcription factors, such as NF-κB and nuclear factor of activated-T cells (NFAT),
that are essential for adaptive immunity. Most importantly, nuclear translocated NFAT differentially engages its
binding partners to promote the activation, differentiation, anergy/exhaustion, and effector functions of various T
cell subsets. Notably, tonic signaling and exhaustion observed in CAR-T cell therapy are associated with
hyperactive Ca2+/NFAT signaling. Till now, no FDA-approved CRAC channel blockers are in hand to modulate
the CRAC channel for therapeutic applications. There remains, therefore, a critical need to exploit novel
interventional approaches by targeting the distal CRAC channels in T cells. Unlike most existing studies centered
on CAR per se or the proximal signaling components in modulating CAR-T cell activation pathway, this project
focuses on engineering the distal end of lymphocyte activation pathway without any modifications to the chimeric
antigen receptor or proximal TCR signaling. The m-PIs propose to to develop a suite of genetically-encoded
CRAC channel Blockers (CRAB) that can be precisely controlled by light or drugs (LiCRAB for Aim 1, and
DiCRAB for Aim 2, respectively), thereby conferring tight control of T cell activity to fine-tune T cell efficacy and
mitigate CAR-T cell tonic signaling and/or exhaustion. The successful execution of this project will explore
innovative immunoengineering approaches to accelerate the design of intelligent cell-based therapies for human
disease. Mechanistically, the tools can be utilized to probe the kinetic requirement of Ca2+/NFAT signaling during
CAR-T cell activation. From a translational perspective, we will generate broadly-applicable genetically-encoded
tools for therapeutic T cell functional tuning, which hold great promise to overcome tonic signaling / exhaustion,
and curtail cytokine storm associated with existing FDA-approved CAR T-cell therapies.
项目摘要/摘要。嵌合抗原受体(CAR) T细胞为基础的免疫疗法
项目成果
期刊论文数量(0)
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Guolin Ma其他文献
Guolin Ma的其他文献
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{{ truncateString('Guolin Ma', 18)}}的其他基金
Optogenetic toolkit for precise control of organellar calcium signaling
用于精确控制细胞器钙信号传导的光遗传学工具包
- 批准号:
10388807 - 财政年份:2022
- 资助金额:
$ 22.76万 - 项目类别:
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