免疫抑制受体SIRL-1调控吞噬细胞固有免疫应答促进RA发病的作用及机制

批准号:
81971535
项目类别:
面上项目
资助金额:
52.0 万元
负责人:
范列英
依托单位:
学科分类:
自身免疫性疾病
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
范列英
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中文摘要
白细胞表面信号抑制受体-1(SIRL-1)是新发现的免疫抑制受体,表达在固有免疫吞噬及抗原提呈细胞上,能抑制FcR介导的活性氧产生和肽精氨酸脱亚氨基酶4(PADI4)移位而阻止自杀式中性粒细胞(PMN)外捕网形成(sNETosis)。类风湿性关节炎(RA)sNETosis增多是引起RA发病重要因素,但原因不明。课题组前期发现活动期RA外周血细胞PADI4表达增加而SIRL-1表达降低,提示与sNETosis增多及抗原提呈异常有关。本项目继续深入,首先用临床样本阐明PBMCs中SIRL-1表达分布及基因多态性与RA发病相关性,流式细胞和激光共聚焦分析SIRL-1表达对sNETosis和细胞吞噬、抗原提呈的影响及信号通路;采用SIRL-1单抗和PADI4-siRNA纳米载体在细胞和动物模型上探讨单独调控SIRL-1或联合调控PADI4的精准靶向策略对上述细胞功能以及在RA防治中作用。
英文摘要
Signal inhibitory receptor on leukocytes-1(SIRL-1) is a novel functional inhibitory immune receptor expressed on human neutrophils and most monocytes, and some myeloid dendritic cells (mDC). The study found that SIRL-1 inhibits FcR-mediated NADPH oxidase-dependent reactive oxygen species (ROS) production and peptide arginine deamidase 4 (PADI4) translocation, thereby preventing the formation of suicidal neutrophil extracellular traps (suicidal NETosis ). SIRL-1high monocytes produce less TNF-α than SIRL-1low monocytes. A single SNP, rs612529T/C, located in the promoter of VSTM1 (SIRL-1), the protein level of SIRL-1 is strongly associated with genotype of this SNP, the people with low expression genotypes are associated with susceptibility to atopic dermatitis.. The studies have shown that suicidal NETosis is a double-edged sword. Although it plays an important role in removing harmful substances such as pathogens, improper release of various enzymes and proteins in cells may cause tissue damage, inflammation and induce autoimmune diseases. Increased suicidal NETosis in rheumatoid arthritis (RA) is an important cause of RA, but the cause is unknown. Our previous study found that the expression of PADI4 in RA PBMCs increased and the expression of SIRL-1 decreased, suggesting that it is associated with increased suicidal NETosis and abnormal antigen presentation. This study will continue to explore the following research work: 1. Using fluorescent antibody technique, to clarify SIRL-1 expression in PBMCs, analysis of the relationship between SIRL-1 gene polymorphism and RA susceptibility. 2. Flow cytometry and laser confocal analysis were used to analyze the effect of SIRL-1 expression on suicidal NETosis, phagocytosis and antigen presentation. 3. SIRL-1 monoclonal antibodies and PADI4-siRNA nanocarriers to explore the precise targeting strategy of the regulation of SIRL-1 alone or joint regulation of PADI4 in cell and animal models to regulate these cell functions and prevent and treat RA.
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DOI:10.1016/j.molimm.2022.09.008
发表时间:2022-09
期刊:Molecular immunology
影响因子:3.6
作者:Lan Wang;J. Yuan;Yu Cheng;Zhenglei Xu;Menglei Ding;Jing Li;Yuying Si;M. Zong;L. Fan
通讯作者:Lan Wang;J. Yuan;Yu Cheng;Zhenglei Xu;Menglei Ding;Jing Li;Yuying Si;M. Zong;L. Fan
DOI:10.3760/cma.j.cn114452-20220413-00223
发表时间:2022
期刊:中华检验医学杂志
影响因子:--
作者:袁佳仪;李锦;范列英
通讯作者:范列英
DOI:10.3969/j.issn.1000-484x.2022.13.015
发表时间:2022
期刊:中国免疫学杂志
影响因子:--
作者:王岚;袁佳仪;司玉莹;陈念贞;宗明;范列英
通讯作者:范列英
DOI:10.3389/fmicb.2023.1157403
发表时间:2023
期刊:Frontiers in microbiology
影响因子:5.2
作者:
通讯作者:
DOI:10.3760/cma.j.cn114452-20220720-00420
发表时间:2022
期刊:中华检验医学杂志
影响因子:--
作者:袁佳仪;王岚;徐学静;徐臻;宗明;虞珊珊;陆英;谭琪;范列英
通讯作者:范列英
PADI4调控巨噬细胞极化和增殖在RA关节滑膜病变中的作用及分子机制
- 批准号:81671599
- 项目类别:面上项目
- 资助金额:57.0万元
- 批准年份:2016
- 负责人:范列英
- 依托单位:
G6PI介导RA关节滑膜增生与血管新生的作用及分子机制
- 批准号:81373203
- 项目类别:面上项目
- 资助金额:70.0万元
- 批准年份:2013
- 负责人:范列英
- 依托单位:
基于组蛋白甲基化/瓜氨酸化修饰途径探讨PADI4在类风湿关节炎滑膜增生中的作用
- 批准号:81072467
- 项目类别:面上项目
- 资助金额:31.0万元
- 批准年份:2010
- 负责人:范列英
- 依托单位:
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