Cis-interaction mediated CD28 costimulation

顺式相互作用介导的 CD28 共刺激

• 批准号: 10371732
• 负责人: Yunlong Zhao
• 金额: $ 12.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371732
• 关键词: Ablation; Address; Affect; Antigen-Presenting Cells; Ants; Award; Binding; Biological Assay; CD28 gene; California; Career Mobility; Cell Communication; Cells; Chronic Disease; Communicable Diseases; Cytomegalovirus Infections; Data; Development Plans; Dimensions; Dissection; Ensure; Environment; Equilibrium; Fluorescence Resonance Energy Transfer; Foundations; Goals; Health; Human; Immune; Immune response; Immunologic Receptors; Immunotherapy; In Vitro; Infection; Interleukin-2; Investigation; Knowledge; Lead; Life; Ligands; Liposomes; Malignant Neoplasms; Measures; Mediating; Membrane; Mentorship; Microscopy; Modeling; Molecular; Murid herpesvirus 1; Mus; Mutagenesis; Oncogenic Viruses; PTPRC gene; Paper; Pathway interactions; Peripheral; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Positioning Attribute; Production; Proteins; Publishing; Receptor Activation; Receptor Signaling; Research; Research Personnel; Research Training; Resolution; Resource Development; Role; Series; Signal Pathway; Signal Transduction; Solid; System; T cell regulation; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Therapeutic; Tissues; Training; Universities; Viral; Virus; Virus Diseases; Western Blotting; antigen-specific T cells; base; career; career development; cytokine; effector T cell; experimental study; immune checkpoint blockade; improved; in vivo; innovation; insight; neoplastic cell; novel; overexpression; post-doctoral training; receptor; reconstitution; recruit; success; tool; tumor

Project Summary Engagement of CD28 provides a critical costimulatory signal for T cell activation. Absence of adequate CD28 costimulation is a common feature of dysfunctional T cells in cancer and viral infections. However, although augmentation of CD28 signaling is well known to be essential for restoring dysfunctional T cells protective immune responses upon immune checkpoint blockade treatment, it is unclear how CD28 in those T cells is activated in the absence of corresponding ligands on cancer and virus-infected cells, indicating the limited mechanistic understanding of the B7:CD28 pathway. My preliminary data have suggested a novel mechanism of CD28 activation by B7 on the same T cell (cis-B7:CD28 interactions), different from the known CD28 engagement by B7 on antigen-presenting cells (trans-B7:CD28 interactions). This finding has begun to reveal a unique avenue to trigger CD28 signaling in effector T cells for vigorous anti-tumor and ant-virus immune responses. Based on this finding, the objective of this K99/R00 application is to understand the function and mechanism of cis-B7:CD28 interaction and leverage cis-activation of CD28 to enhance the activity of T cells against cancer and infection. To this end, I propose the following aims: Aim 1: Establish a role of B7:CD28 cis- interactions in regulating T cells activity. Aim 2: Dissect the molecular mechanism through which CD28 is activated by B7 ligands in cis. Aim 3: Identify the function of cis-B7:CD28 interaction in T cell immune response against tumor and viral infection. These three aims will allow me to perform a comprehensive investigation on cis-B7:CD28 interactions and the knowledge gained from this study will likely provide valuable therapeutic implications in CD28 targeted T cell therapy. I have a strong background in studying cis-interactions and their functions in regulating T cell activity, which is evidenced by publishing two impactful papers during my postdoctoral training. Importantly, I have established a series of unique and robust approaches to convincingly decouple cis- and trans-interactions in coreceptors signaling. This has been the solid foundation of my proposed experiments. Moreover, my mentorship committee and I have developed an individualized research training and career development plan, which helps me obtain additional skillsets and expertise and ultimately ensures my success in seeking an independent investigator position. University of California, San Diego provides the best possible environment for my K99 research, including world-leading research, cutting-edge facilities and extensive career development resources. Overall, this K99/R00 award will fulfill my career goal to understand the function and mechanism of costimulatory receptor signaling in regulation of T cell activity and promote my career transition into an independent investigator.

项目摘要 CD28的参与为T细胞激活提供了关键的共刺激信号。没有足够的CD28 共刺激是癌症和病毒感染中功能失调T细胞的常见特征。但是，虽然 CD28信号的增强对于恢复功能失调的T细胞保护性至关重要 免疫应答后，免疫检查点阻滞处理治疗，尚不清楚这些T细胞中的CD28如何 在没有癌症和病毒感染细胞的相应配体的情况下被激活，表明有限 B7：CD28途径的机械理解。我的初步数据提出了一种新颖的机制 B7在同一T细胞上激活CD28（顺式B7：CD28相互作用），与已知的CD28不同 B7参与抗原呈递细胞（Trans-B7：CD28相互作用）。这一发现开始揭示 在效应T细胞中触发CD28信号传导的独特途径，以进行剧烈抗肿瘤和蚂蚁病毒免疫 回答。基于这一发现，此K99/R00应用程序的目的是了解该功能和 顺式-B7的机理：CD28的相互作用和利用CD28的顺式激活来增强T细胞的活性 反对癌症和感染。为此，我提出以下目的：目标1：确定B7：CD28顺式的角色 调节T细胞活性的相互作用。 AIM 2：剖析CD28的分子机制 在顺式中被B7配体激活。 AIM 3：确定CIS-B7：CD28在T细胞免疫反应中相互作用的功能 反对肿瘤和病毒感染。这三个目标将使我能够对 顺式-B7：CD28相互作用以及这项研究所获得的知识可能会提供有价值的治疗性 CD28靶向T细胞疗法的含义。我在研究顺式相互作用及其方面有很强的背景 调节T细胞活性的功能，这可以通过在我的期间发表两篇有影响力的论文来证明 博士后培训。重要的是，我已经建立了一系列独特而强大的方法来令人信服 在共感受器信号传导中切除顺式和反式相互作用。这是我提议的坚实基础 实验。此外，我和我的指导委员会已经开发了个性化的研究培训， 职业发展计划，这有助于我获得其他技能和专业知识，并最终确保我的 成功寻求独立研究者职位。加利福尼亚大学圣地亚哥提供了最好的 我的K99研究的可能环境，包括世界领先的研究，尖端设施和 广泛的职业发展资源。总体而言，这项K99/R00奖将实现我的职业目标来了解 在调节T细胞活性调节中的共刺激受体信号传导的功能和机制并促进我 职业过渡到独立调查员。