Roles of TRAF3 in myeloid derived suppressor cells in chronic inflammation

TRAF3 在慢性炎症中骨髓源性抑制细胞中的作用

• 批准号: 9387608
• 负责人: PING XIE
• 金额: $ 19.38万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-07 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9387608
• 关键词: Address; Aging; Applications Grants; Autoimmune Diseases; Biochemical; Bioinformatics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell physiology; Chronic; Communicable Diseases; Complex; Cytoplasmic Protein; Data; Development; Disease; Employee Strikes; Exhibits; Generations; Goals; Immune response; Immune system; Immunologic Receptors; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Knowledge; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Pathogenesis; Pilot Projects; Play; Prevention; Process; Public Health; Regulation; Research; Role; Signal Pathway; Signal Transduction; Solid; Suppressor-Effector T-Lymphocytes; TNF receptor-associated factor 3; Testing; Therapeutic; Transducers; adaptive immunity; base; cell type; design; human disease; in vivo; innovation; insight; macrophage; mouse model; new therapeutic target; novel; novel therapeutics; therapeutic target; therapy development; tumor

Summary Myeloid-derived suppressor cells (MDSCs) are crucial drivers of chronic inflammation and potent suppressors of immune responses. Aberrant expansion and dysregulated functions of MDSCs contribute to the pathogenesis of numerous human diseases involving chronic inflammation. MDSCs are recognized as an important therapeutic target for these diseases, and Intensive efforts are currently directed at developing therapies to inhibit the expansion of MDSCs and to block the functions of MDSCs. Identification of new regulators of MDSCs is thus critical for the development of such novel therapies. This exploratory proposal aims to elucidate the roles and signaling mechanisms of a novel emerging regulator of MDSCs, TRAF3, a signal transducer of a variety of immune receptors. By examining a new mouse model that has TRAF3 specifically deleted in myeloid cells (M-TRAF3-/- mice), we recently found that TRAF3 inhibits chronic inflammation and infection likely through controlling the expansion of MDSCs. In strong corroboration of our findings, increasing evidence indicates that a number of TRAF3-employing immune receptors directly regulate the expansion and/or suppressive activities of MDSCs. Despite its likely importance, the direct roles of TRAF3 in MDSCs remain unknown. We will address this significant gap in knowledge in the current proposal. Based on our new findings and preliminary results, we will test the central hypothesis that TRAF3 and TRAF3-dependent signaling pathways directly control the expansion and suppressive functions of MDSCs, thereby inhibiting chronic inflammation. To address this, we propose complementary in vitro and in vivo studies to decipher the cellular and molecular mechanisms underlying TRAF3-mediated regulation of MDSCs. Importantly, we will identify the intrinsic signaling pathways of immune receptor(s) that play dominant roles in the TRAF3-dependent processes in MDSCs. Our long-term goal is to gain new insights into the regulatory mechanisms of MDSC physiology as well as MDSC-mediated chronic inflammation and immunosuppression in disease pathogenesis. Such knowledge will pave the way towards developing innovative therapeutic strategies to manipulate TRAF3 signaling pathways in MDSCs for the treatment of chronic inflammatory diseases, cancers, autoimmune diseases, and chronic infectious diseases.

总结 骨髓源性抑制细胞（MDSC）是慢性炎症的关键驱动因素， 免疫反应的抑制剂。MDSC的异常扩增和功能失调有助于 涉及慢性炎症的许多人类疾病的发病机制。MDSC被认为是 这些疾病的重要治疗靶点，目前正在集中努力开发 抑制MDSC扩增和阻断MDSC功能的治疗。确定新 因此，MDSC的调节剂对于开发这种新疗法至关重要。这个探索性的提议 目的是阐明一种新的MDSC调节因子TRAF 3的作用和信号机制， 多种免疫受体信号转导子。通过研究一种新的小鼠模型， 在骨髓细胞中特异性缺失（M-TRAF 3-/-小鼠），我们最近发现TRAF 3抑制慢性 炎症和感染可能是通过控制MDSC的扩增来实现的。这有力地证实了我们 越来越多的证据表明，一些TRAF 3-使用免疫受体直接 调节MDSC的扩增和/或抑制活性。尽管其可能的重要性， TRAF 3在MDSC中的表达仍然未知。我们将在目前的知识中解决这一重大差距， 提议基于我们的新发现和初步结果，我们将检验TRAF 3 和TRAF 3依赖性信号通路直接控制的扩张和抑制功能， MDSC，从而抑制慢性炎症。为了解决这一问题，我们建议在体外和体内进行补充。 体内研究，以破译TRAF 3介导的调节的细胞和分子机制， MDSC。重要的是，我们将确定免疫受体的内在信号通路， 在MDSC中TRAF 3依赖性过程中起主导作用。我们的长期目标是获得新的见解， MDSC生理学的调节机制以及MDSC介导的慢性炎症， 免疫抑制在疾病发病机制中作用。这些知识将为发展 创新的治疗策略，以操纵MDSC中的TRAF 3信号通路， 慢性炎性疾病、癌症、自身免疫性疾病和慢性感染性疾病。