Exploratory Study of T Cell Skin Trafficking and the Role of NKG2D Signaling; Implications in Vitiligo and Melanoma

T 细胞皮肤贩运和 NKG2D 信号传导作用的探索性研究；

• 批准号: 10608358
• 负责人: Jose Alejandro Guevara-Patino
• 金额: $ 40.78万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608358
• 关键词: Address; Affect; Autoimmune; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cells; Cellular Structures; Complex; Cytotoxic T-Lymphocytes; Data; Development; Engineering; Ensure; Flow Cytometry; Gene Expression Profiling; Genes; Genetic Engineering; Genetic Transcription; Home; Homing; Human; Immunology; Individual; Knockout Mice; Mediating; Memory; Microscopy; Molecular; Mus; PIK3CG gene; Participant; Patients; Play; Prognostic Factor; Property; Proteins; Regulatory Element; Repression; Research; Research Design; Research Support; Role; Signal Transduction; Skin; Skin Cancer; Sum; T cell differentiation; T memory cell; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Tissues; Transcription Factor AP-1; Transgenic Mice; Vitiligo; Western Blotting; Work; adaptive immunity; autoreactive T cell; cell motility; chemokine receptor; chromatin immunoprecipitation; clinical application; design; engineered T cells; gp100 Antigen; human model; in vivo; innovation; insight; melanocyte; melanoma; migration; mouse model; mutant; novel; pathogen; promoter; receptor; recruit; small hairpin RNA; trafficking; transcription factor; transplant model; tumor growth

Abstract In the field of immunology, T cell migration is considered crucial for long-term host survival. However, the identity of the players that participate and the mechanistic relationships in this complex network remain to be fully established, especially in the context of vitiligo and melanoma. Our understanding of the T cell migratory properties and initiation ques may help find clinically applicable treatments to vitiligo and melanoma. Based on novel preliminary data, we propose to study NKG2D signaling as a contributor to T cell trafficking. The scientific premise of this study is derived from our work demonstrating that lack of NKG2D reduces T cell tmigration and expression of CCR4. We hypothesize that NKG2D controls CD8 T cell trafficking through a finely tuned DAP10PI3K/Grb2 signaling (as NKG2D cannot signal by itself instead of using DAP10PI3K/Grb2 as signaling adaptor) that controls the expression of CCR4. This proposal will define the underlying roles of NKG2D-DAP10PI3K and -DAP10Grb2 in CD8 T cell trafficking and the expression control of CCR4. Here we will conduct experimental tests utilizing human and mouse models. SA1. TO DETERMINE THE SIGNALING PATH FOR NKG2D-DAP10PI3K and/or -DAP10Grb2 THAT CONTROLS CCR4 EXPRESSION. SA2. TO DETERMINE THE SPECIFIC CONTRIBUTION OF NKG2D-DAP10PI3K and/or -DAP10Grb2 SIGNALING IN THE SKIN TRAFFIC OF CD8 T CELLS.

抽象的 在免疫学领域，T细胞迁移被认为对于宿主的长期生存至关重要。然而，该人的身份 这个复杂网络中的参与主体和机制关系仍有待完全建立，特别是 在白癜风和黑色素瘤的背景下。我们对 T 细胞迁移特性和启动问题的了解可能会有所帮助 寻找临床适用的白癜风和黑色素瘤治疗方法。基于新的初步数据，我们建议研究 NKG2D 信号传导作为 T 细胞运输的贡献者。这项研究的科学前提源自我们的工作 证明缺乏 NKG2D 会降低 T 细胞迁移和 CCR4 的表达。我们假设 NKG2D 通过精细调节的 DAP10PI3K/Grb2 信号传导控制 CD8 T 细胞运输（因为 NKG2D 无法自行发出信号 使用 DAP10PI3K/Grb2 作为信号适配器）控制 CCR4 的表达。该提案将定义基础 NKG2D-DAP10PI3K 和 -DAP10Grb2 在 CD8 T 细胞运输和 CCR4 表达控制中的作用。在这里我们将 利用人类和小鼠模型进行实验测试。 SA1。确定控制 NKG2D-DAP10PI3K 和/或 -DAP10Grb2 的信号路径 CCR4 表达。 SA2。确定 NKG2D-DAP10PI3K 和/或 -DAP10Grb2 的具体贡献 CD8 T 细胞皮肤交通中的信号传导。