Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands
使用 CAR 和肽-MHC 嵌合抗原配体精确靶向 T1D 特异性 T 细胞
基本信息
- 批准号:10436483
- 负责人:
- 金额:$ 72.85万
- 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:2022-05-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAnimal ModelAntigen TargetingAntigensAutoantigensAutoimmune DiseasesAutoimmune ResponsesAutoimmunityBeta CellBindingBiological ModelsBlood GlucoseCAR T cell therapyCell TherapyCellsClinicalCollaborationsCollectionCore FacilityCytoprotectionDataDiabetic mouseEngineeringEpitopesExperimental DesignsFailureFutureGoalsHematologic NeoplasmsHematopoietic NeoplasmsHumanHuman CloningImmune TargetingImmune mediated destructionImmune systemImmunologyImmunosuppressionIn VitroInsulin-Dependent Diabetes MellitusIslet CellLifeLigandsMapsMemoryModelingMusOutcomePatientsPeptide/MHC ComplexPeptidesPerformanceReagentSignal TransductionSourceSpecificitySpecimenStructureSystemT-LymphocyteTechniquesTechnologyTestingWorkantigen bindingautoreactive T cellautoreactivitycell killingchimeric antigen receptorchimeric antigen receptor T cellsclinical efficacyclinical implementationdesignexhaustionexperimental studyflexibilityhumanized mouseimprovedin vitro Assayin vivoisletmannovelpreventrecruitstandard caresynthetic biology
项目摘要
Project Summary
Type 1 diabetes (T1D) is an incurable autoimmune disease manifested through the immune destruction of islet
beta cells. This proposal describes a unique CAR T cell approach to eliminate islet-autoreactive T cells, thus
eliminating the source of the autoimmunity and providing a highly specific treatment for T1D. We will leverage
our recently developed split CAR system with a chimeric antigen ligand (CAL) adaptor consisting of a pMHC
multimer fused to a recruitment molecule. The addition of CAL will bind to the autoreactive TCR and recruit the
universal CAR T cells to kill autoreactive T1D specific T cells. The proposed experiments will test the hypoth-
eses that (1) our modular CAR/CAL systems are uniquely suited for specifically targeting multiple auto-
reactive TCRs, and (2) that we can identify novel epitopes against T1D specific TCRs to be paired with
the CAR/CAL system. Importantly, preliminary data support these hypotheses, and well-characterized clinical
specimens from T1D patients and rigorous experimental designs are established in this proposal with essential
cross-disciplinary collaborations and expertise that encompass synthetic biology, large-scale epitope discovery,
T1D immunology, and humanized T1D animal modeling. The specific aims of this five-year proposal are as
follows: Aim 1 establish and optimize the CAL system against antigen-specific human TCRs, Aim 2 characterize
the autoreactivity of TCRs from T1D patients/donors and identify peptide-MHC against these TCRs, and Aim 3
evaluate the performance of the CAL system in humanized T1D animal models. Outcomes from this work will
establish the clinical potential of the CAR/CAL system as a safe, effective, and potentially curative T1D treatment.
项目摘要
1型糖尿病(T1 D)是一种无法治愈的自身免疫性疾病,表现为胰岛细胞的免疫破坏,
β细胞该提案描述了一种独特的CAR T细胞方法来消除胰岛自身反应性T细胞,
消除了自身免疫的来源,并为T1 D提供了高度特异性的治疗。我们将利用
我们最近开发的具有嵌合抗原配体(CAL)衔接子的分裂CAR系统由pMHC
多聚体与募集分子融合。CAL的添加将结合自身反应性TCR并募集免疫应答。
通用CAR T细胞杀死自身反应性T1 D特异性T细胞。这些实验将检验假设-
(1)我们的模块化CAR/CAL系统是唯一适合专门针对多个汽车,
反应性TCR,以及(2)我们可以鉴定针对T1 D特异性TCR的新表位,以与
CAR/CAL系统。重要的是,初步的数据支持这些假设,
T1 D患者的标本和严格的实验设计建立在这个建议与基本的
跨学科合作和专业知识,包括合成生物学,大规模表位发现,
T1 D免疫学和人源化T1 D动物建模。这一五年计划的具体目标是:
目的1建立并优化针对抗原特异性人TCR的CAL体系,目的2表征
来自T1 D患者/供体的TCR的自身反应性和鉴定针对这些TCR的肽-MHC,以及Aim 3
评价CAL系统在人源化T1 D动物模型中的性能。这项工作的成果将
确立CAR/CAL系统作为安全、有效和潜在治愈性T1 D治疗的临床潜力。
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 }}
Michael Birnbaum其他文献
Michael Birnbaum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('Michael Birnbaum', 18)}}的其他基金
Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands
使用 CAR 和肽-MHC 嵌合抗原配体精确靶向 T1D 特异性 T 细胞
- 批准号:
10621960 - 财政年份:2022
- 资助金额:
$ 72.85万 - 项目类别:
Development of an emulsion-based method for repertoire-scale paired-chain T cell receptor sequencing
开发基于乳剂的全谱配对链 T 细胞受体测序方法
- 批准号:
10371136 - 财政年份:2021
- 资助金额:
$ 72.85万 - 项目类别:
Repertoire-scale T cell antigen identification via peptide-MHC lentivirus display
通过肽-MHC 慢病毒展示进行全库规模 T 细胞抗原鉴定
- 批准号:
10001123 - 财政年份:2020
- 资助金额:
$ 72.85万 - 项目类别:
Determining antigen recognition in systemic sclerosis
确定系统性硬化症中的抗原识别
- 批准号:
10188400 - 财政年份:2014
- 资助金额:
$ 72.85万 - 项目类别:
Determining antigen recognition in systemic sclerosis
确定系统性硬化症中的抗原识别
- 批准号:
9915867 - 财政年份:
- 资助金额:
$ 72.85万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 72.85万 - 项目类别:
Continuing Grant