Exploiting the Mechanobiology of PD-1 for Cancer Immunotherapy

利用 PD-1 的力学生物学进行癌症免疫治疗

• 批准号: 10381102
• 负责人: Rafi Ahmed
• 金额: $ 7.6万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381102
• 关键词: Affect; Alopecia Areata; Antigens; Applications Grants; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; CD8-Positive T-Lymphocytes; Cell Survival; Cell physiology; Cells; Communicable Diseases; Complex; Cytotoxic T-Lymphocytes; DNA; Devices; Disease; Future; Goals; Grant; Hair; Hair follicle structure; Human; Image; Immune; Immune Tolerance; Immunologics; Immunotherapy; In Situ; Individual; Infiltration; Inflammatory Response; Knowledge; Libraries; Ligands; Major Histocompatibility Complex; Malignant Neoplasms; Measures; Mechanics; Methods; Microfluidics; Modeling; Mus; Pathogenicity; Pathology; Patients; Peptides; Population; Reaction; Receptor Signaling; Regulation; Reporting; Research; Role; Signal Transduction; Stains; Structure; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCR Activation; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Work; base; black women; cancer immunotherapy; career; cytotoxic CD8 T cells; exhaustion; experience; human model; immune checkpoint; improved; melanoma; molecular dynamics; mouse model; novel strategies; parent grant; parent project; physical science; programmed cell death ligand 1; programmed cell death protein 1; protein aminoacid sequence; response; single bond; single cell sequencing; single molecule; tool; tumor

Project Summary Alopecia Areata (AA) is an autoimmune disease affecting ~2% of the world population, especially affecting black women disproportionately, with no cure at the present time. It manifests as inflammatory response of the hair follicles where immune cells, cytotoxic T cells in particular, attack self-tissue, resulting in hair loss. The mechanism underlying this autoimmune reaction is incomplete understood, and the disease-driving antigens recognized by the specific T-cell receptors (TCR) are not known. The objectives of this project are to identify and characterize Alopecia Areata-specific and force sensitive antigen and cognate TCRs. It is widely accepted that the disease is induced by a loss of immune privilege in hair follicles, leading to the loss of immune tolerance of a subpopulation of CD8+ T cells that recognize self-antigens. We hypothesize that the self-antigen peptide-histocompatibility complex (pMHC) interaction with TCR is stronger than those that provide tonic signals for T cell survival but weaker than the pathogenic-pMHC-TCR interactions. The two specific aims are: 1) To identify AA-driving antigens and their cognate TCRs in human and mouse using a newly developed pMHC-tetramer library-stained single-cell sequencing technique. 2) To characterize the force-dependent AA-pMHC-TCR interaction and compare it with self- and pathogenic- pMHC-TCR interactions using the biomembrane force probe technology of the Zhu lab. Completing these aims will pave the way for future studies investigating TCR signaling induced by pMHC, the resulting T-cell activation/function, improved transgenic TCR mouse models for AA, and an eventual cure.

项目摘要 斑秃（AA）是一种自身免疫性疾病，影响约2%的世界人口，特别是影响 黑人妇女比例过高，目前无法治愈。它表现为炎症反应， 毛囊中的免疫细胞，特别是细胞毒性T细胞，攻击自身组织，导致脱发。的 这种自身免疫反应的机制尚不完全清楚， 由特异性T细胞受体（TCR）识别的细胞因子是未知的。本项目的目标是确定 并表征斑秃特异性和力敏性抗原和同源TCR。人们普遍认为 这种疾病是由毛囊中免疫特权的丧失引起的，导致免疫系统的丧失。 识别自身抗原的CD 8 + T细胞亚群的耐受性。我们假设自体抗原 肽-组织相容性复合物（pMHC）与TCR的相互作用强于那些提供滋补的TCR。 pMHC-TCR是T细胞存活的信号，但弱于病原性pMHC-TCR相互作用。这两个具体目标是： 1)为了使用新开发的方法鉴定人和小鼠中AA驱动抗原及其同源TCR， pMHC-四聚体文库染色的单细胞测序技术。 2)为了表征力依赖性AA-pMHC-TCR相互作用，并将其与自身和致病性 使用Zhu实验室的生物膜力探针技术的pMHC-TCR相互作用。 完成这些目标将为未来研究pMHC诱导的TCR信号传导铺平道路， 由此产生的T细胞活化/功能，改善的AA转基因TCR小鼠模型，以及最终治愈。