Elucidating the Role of Neuropilin-1 in Intratumoral Regualtory T Cell Stability

阐明 Neuropilin-1 在瘤内调节性 T 细胞稳定性中的作用

• 批准号: 9070295
• 负责人: Abigail E Overacre-Delgoffe
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070295
• 关键词: Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autoimmunity; Binding; Biochemistry; Biological; Cancer Biology; Cancer Patient; Cell Nucleus; Cell physiology; Cells; Chronic; Data; Environment; Equilibrium; Exhibits; Fatty acid glycerol esters; Flow Cytometry; Genes; Genetic; Genotype; Goals; Heterozygote; IFNGR1 gene; Immune response; Immune system; Immunity; Immunoblotting; Immunologic Techniques; Immunotherapy; Infection; Inflammatory; Interferon Type II; Lead; Ligand Binding; Ligands; Ligation; Malignant Neoplasms; Mediating; Mediator of activation protein; Methylation; Modeling; Molecular; Mus; Neuropilin-1; Pathway interactions; Phenocopy; Phenotype; Play; Population; Proto-Oncogene Proteins c-akt; Regulatory T-Lymphocyte; Research; Research Proposals; Resistance; Role; Rosa; Semaphorins; Signal Transduction; Surface; System; T-Lymphocyte; Tissues; Training; Tumor Immunity; X Chromosome; X Inactivation; base; cancer immunotherapy; career; cytokine; gain of function; melanoma; mouse model; outcome forecast; pathogen; prevent; public health relevance; receptor; research study; response; transcription factor; tumor; tumor growth; tumor immunology; tumor microenvironment

 DESCRIPTION (provided by applicant): The adaptive immune system serves to eliminate pathogens while sparing host tissue. The efficiency of this system is largely dependent on balance; unrestrained immunity can cause autoimmunity while a slow or absent response can lead to chronic infection and cancer. Regulatory T cells (Tregs) play a critical role in maintainin this balance through the suppression of self-reactive immune responses. Treg stability is crucial to maintain effective suppressive capacity. Neuropilin-1 (Nrp1), a surface receptor has emerged as an important mediator of Treg stability. Nrp1 binds the ligand, Semaphorin-4a (Sema-4a), leading to enhanced Treg stability intratumorally. In the absence of Nrp1:Sema4a ligation, Tregs lose stability and suppressive capabilities, leading to enhanced anti-tumor immunity and reduced tumor growth. The fate and function of Nrp1-deficient Tregs is unclear. This research proposal suggests experiments that will propel our understanding of how Nrp1 alters Treg stability, and will elucidate the molecular mechanisms leading to a distinct Treg cell population and reduced tumor growth. Understanding these mechanisms is of crucial importance in understanding tumor immunology, and in creating new targets for immunotherapy.

 描述（由申请人提供）：适应性免疫系统用于消除病原体，同时保留宿主组织。该系统的效率在很大程度上取决于平衡;无限制的免疫可能导致自身免疫，而缓慢或缺乏反应可能导致慢性感染和癌症。调节性T细胞（TCLs）通过抑制自身反应性免疫应答在这种平衡中发挥关键作用。Treg稳定性对于维持有效的抑制能力至关重要。神经纤毛蛋白-1（Nrp 1）是一种表面受体，已成为调节Treg稳定性的重要介质。Nrp 1结合配体Semaphorin-4a（Sema-4a），导致肿瘤内Treg稳定性增强。在Nrp 1：Sema 4a连接不存在的情况下，TcB失去稳定性和抑制能力，导致增强的抗肿瘤免疫力和减少的肿瘤生长。Nrp 1缺陷型TcB的命运和功能尚不清楚。这项研究建议的实验将促进我们对Nrp 1如何改变Treg稳定性的理解，并将阐明导致不同Treg细胞群和减少肿瘤生长的分子机制。了解这些机制对于理解肿瘤免疫学和创造免疫治疗的新靶点至关重要。