Unmasking the Immunomodulatory Roles of CD7 Signaling

揭示 CD7 信号传导的免疫调节作用

• 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
• 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' 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

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.

项目总结/摘要 该NIAID R 01提案描述了Wan-Lin Lo博士，将解决信号 她在犹他州大学的独立实验室研究了T细胞中CD 7的特性和生理功能 医学院的。虽然以前的研究将CD 7视为非必需的共刺激分子，但CD 7的表达与CD 8的表达无关。 该提案的初步结果表明，CD 7支持T细胞受体（TCR）信号传导和效应子 功能：CD 7可能以配体非依赖性方式作为TCR的主要PI 3 K募集支架蛋白发挥作用 并作为降低TCR活化阈值的共刺激受体。卢博士设想CD 7是一部小说， 在一些实施方案中，本发明涉及用于调节感染、癌症和自身免疫性疾病中的T细胞功能的免疫调节靶标。 该提案的总体目标是表征CD 7用于促进T细胞活化的机制。 目的：探讨靶向CD 7以增强或减轻T细胞效应因子的可能性。 功能第一个目标是研究急性和慢性炎症过程中T细胞中CD 7参与的信号传导的影响。 在蛋白质组、转录组和表观遗传水平上的病毒感染，假设CD 7扩增 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 细胞对弱配体的反应。第二个目标将定义在CD 7不存在的情况下T细胞命运的改变。 急性和慢性病毒感染，以检验CD 7参与的信号传导对于促进抗病毒治疗至关重要的假设。 T细胞效应子功能，并且需要最佳水平的CD 7信号传导来防止T细胞耗竭， CD 7高反应性或避免由于缺乏CD 7而导致的T细胞无反应性。本研究的目的 是解决目前免疫调节治疗的障碍（即，T细胞耗竭与自身免疫 毒性）。该提案的重点与NIAID的使命高度相关，并将加强我们的 了解感染期间T细胞命运决定的信号机制，特别是 固有的、特征性的蛋白质组学适应和表观遗传重编程，其增强T细胞身份。 最终，这项工作将有助于设计和开发针对CD 7的治疗方法，并增强未来的治疗效果。 这些研究旨在评估CD 7调节的T细胞功能适应如何在各种疾病环境中调节。