Unmasking the Immunomodulatory Roles of CD7 Signaling

揭示 CD7 信号传导的免疫调节作用

基本信息

批准号：
10637876
负责人：
Wan-Lin Lo
金额：
$ 53.38万
依托单位：
UNIVERSITY OF UTAH
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：
2023-07-20 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10637876
关键词：
Acute Adaptor Signaling Protein Address Adoptive Transfer Aging Antiviral Response Autoimmune Diseases Binding CD3 Antigens CD7 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell physiology Cells Characteristics Chronic Clinical Complex Cutaneous T-cell lymphoma Data Disease Doctor of Philosophy Epigenetic Process Extracellular Domain Freund&apos s Adjuvant Functional disorder Future Goals HIV/HCV Human Immunity Impairment In Vitro Infection Inflammation Interleukin-2 Laboratories Ligands Link Lymphocytic choriomeningitis virus MHC Interaction Major Histocompatibility Complex Malignant Neoplasms Mission Modeling Molecular Molecular Profiling Monitor Mus National Institute of Allergy and Infectious Disease Outcome Ovalbumin PIK3CG gene PTPRC gene Pathologic Peptide Receptor Peptide/MHC Complex Physiological Production Proliferating Property Proteomics Receptor Activation Receptor Signaling Role SECTM1 gene Scaffolding Protein Sezary Syndrome Signal Transduction Stimulus T cell differentiation T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Transgenic Mice Universities Utah Validation Viral Virus Diseases Work acute infection aged autoimmune toxicity chronic infection cytotoxicity design druggable target effector T cell exhaust exhaustion experimental study functional adaptation immunomodulatory strategy immunomodulatory therapies immunoregulation in vivo medical schools multiple omics mutant novel prevent receptor receptor function recruit release of sequestered calcium ion into cytoplasm scaffold senescence synergism therapeutic development transcriptomics

项目摘要

PROJECT SUMMARY/ABSTRACT This NIAID R01 proposal describes the framework in which Wan-Lin Lo, Ph.D., will address the signaling properties and physiological function of CD7 in T cells in her independent laboratory at the University of Utah School of Medicine. While previous studies have treated CD7 as an inessential costimulatory molecule, the preliminary results in this proposal suggest that CD7 supports T cell receptor (TCR) signaling and effector functions: CD7 may function as a major PI3K-recruiting scaffold protein for the TCR in a ligand-independent way and as a costimulatory receptor that lowers the TCR activation threshold. Dr. Lo envisions that CD7 is a novel immunoregulatory target for the modulation of T cell function in infections, cancers, and autoimmune diseases. The overall goals of this proposal are to characterize the mechanisms used by CD7 to facilitate T cell differentiation during infection and to explore the possibility of targeting CD7 to enhance or mitigate T cell effector function. The first goal will examine the influences of CD7-involved signaling in T cells during acute and chronic viral infection at the proteomic, transcriptomic, and epigenetic levels, with the hypothesis that CD7 amplifies proximal TCR signaling, stabilizes TCR:peptide–major histocompatibility complex interactions, and enhances T cell responses to weak ligands. The second goal will define altered T cell fates in the absence of CD7 during acute and chronic viral infection to test the hypothesis that CD7-involved signaling is essential to promote antiviral T cell effector function, and that an optimal level of CD7 signaling is required to prevent T cell exhaustion due to CD7 hyperreactivity or to avoid T cell unresponsiveness due to the absence of CD7. The objective of this study is to address the current roadblocks to immunomodulatory therapies (i.e., T cell exhaustion and autoimmune toxicities). The focuses of this proposal are highly relevant to the mission of NIAID, and will enhance our understanding of the signaling mechanisms underlying T cell fate decisions during infection, especially the inherent, characteristic proteomic adaptations and epigenetic reprogramming that reinforce T cell identities. Ultimately, this work will aid the design and development of therapeutics to target CD7, and potentiate future studies to assess how CD7-modulated T cell functional adaptation may be regulated in various disease settings.

项目概要/摘要 NIAID R01 提案描述了 Wan-Lin Lo 博士将在其中解决信令问题的框架她在犹他大学的独立实验室研究 T 细胞中 CD7 的特性和生理功能虽然之前的研究将 CD7 视为一种无关紧要的共刺激分子，但该提案的初步结果表明 CD7 支持 T 细胞受体 (TCR) 信号传导和效应器功能：CD7 可能以不依赖配体的方式作为 TCR 的主要 PI3K 招募支架蛋白作为一种降低 TCR 激活阈值的共刺激受体，Lo 博士认为 CD7 是一种新型受体。调节感染、癌症和自身免疫性疾病中 T 细胞功能的免疫调节靶点。该提案的总体目标是表征 CD7 用于促进 T 细胞的机制感染过程中的分化并探索靶向 CD7 增强或减轻 T 细胞效应的可能性第一个目标将检查急性和慢性期间 T 细胞中 CD7 相关信号传导的影响。蛋白质组、转录组和表观遗传水平的病毒感染，假设 CD7 会放大近端 TCR 信号传导，稳定 TCR：肽-主要组织相容性复合物相互作用，并增强 T 第二个目标将定义在缺乏 CD7 的情况下 T 细胞命运的改变。急性和慢性病毒感染，以检验 CD7 相关信号传导对于促进抗病毒至关重要的假设 T 细胞效应功能，并且需要最佳水平的 CD7 信号传导以防止 T 细胞因以下原因而耗竭 CD7 过度反应或避免由于 CD7 缺失而导致的 T 细胞无反应。旨在解决当前免疫调节疗法的障碍（即 T 细胞耗竭和自身免疫该提案的重点与 NIAID 的使命高度相关，并将增强我们的能力。了解感染过程中 T 细胞命运决定的信号机制，尤其是固有的、特征性的蛋白质组适应和表观遗传重编程增强了 T 细胞的特性。最终，这项工作将有助于设计和开发针对 CD7 的疗法，并增强未来的潜力研究评估 CD7 调节的 T 细胞功能适应如何在各种疾病环境中受到调节。