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/文摘