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.

项目摘要/摘要 该NIAID R01提案描述了Wan-lin Lo博士的框架 犹他大学独立实验室T细胞中CD7的特性和身体功能 医学院。虽然先前的研究已将CD7视为实践的共刺激分子，但 该提案的初步结果表明，CD7支持T细胞接收器（TCR）信号传导和效应器 功能：CD7可以作为TCR的主要PI3K恢复支架蛋白，以配体无关的方式起作用 作为降低TCR激活阈值的共刺激接收器。 Lo博士设想CD7是一本小说 在感染，癌症和自身免疫性疾病中调节T细胞功能的免疫调节靶标。 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以增强或减轻T细胞效应器的可能性 功能。第一个目标将检查急性和慢性期间T细胞中CD7涉及信号的影响 蛋白质组学，转录组和表观遗传学水平的病毒感染，假设CD7扩增 TCR近端TCR信号，稳定TCR：肽 - 组织组成性复合物相互作用，并增强T 细胞对弱配体的反应。第二个目标将在不存在CD7的情况下定义改变的T细胞命运 急性和慢性病毒感染以检验CD7涉及信号传导对于促进抗病毒至关重要的假设 T细胞效应子函数，并且需要最佳水平的CD7信号传导才能防止T细胞耗尽 CD7过度反应性或由于缺乏CD7而避免T细胞无反应性。这项研究的目的 要解决当前的障碍，以解决免疫调节疗法（即T细胞耗尽和自身免疫性 毒性）。该提案的重点与Niaid的使命高度相关，并将增强我们的 了解感染过程中T细胞命运决定的信号传导机制，尤其是 固有的，特征性的蛋白质组学适应和表观遗传重编程，以增强T细胞身份。 最终，这项工作将有助于设计和开发治疗剂，以瞄准CD7，并潜在的未来 在各种疾病环境中可以调节CD7调节的T细胞功能适应的研究。