The mammalian sterile 20-like kinase 1 (MST1) is a critical regulator of neutrophil transmigration during inflammation
哺乳动物不育 20 样激酶 1 (MST1) 是炎症过程中中性粒细胞迁移的关键调节因子
基本信息
- 批准号:315921328
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2016
- 资助国家:德国
- 起止时间:2015-12-31 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Leukocyte recruitment during inflammation is an important immunological process enabling leukocytes to leave the intravascular compartment and migrate into inflamed tissue. Recruitment of leukocytes follows a cascade of adhesion and activation events which can roughly be divided into leukocyte rolling, leukocyte adhesion and leukocyte transmigration. Several described inborn immunodeficiency disorders (f.e. leukocyte adhesion deficiency I, LAD-I) lead to a strong reduction in leukocyte recruitment favoring the development of severe bacterial infections. In 2012, three independent groups (including our collaboration partner Prof. Christoph Klein, Children s Hospital LMU Munich) described a new immunodeficiency disorder characterized by a loss-of-function mutation in the mammalian sterile 20-like kinase1 (MST1) gene. Patients with this disorder exhibit frequent recurrent bacterial and viral infections, a pronounced lymphocytopenia, and increased cell apoptosis. In the respective mouse model (Mst1-deficient mice) a severe reduction in lymphocyte adhesion could be shown which is caused by defective mobilization of beta2 integrin LFA-1 containing vesicles to the lymphocyte surface. Currently, studies on adhesion properties of Mst1-deficienct neutrophils (and monocytes) are lacking. Therefore, our research proposal aims to investigate adhesive functions of Mst1-deficient neutrophils in appropriate mouse models and in patients with MST1 deficiency. Our first preliminary results surprisingly show that Mst1-deficient neutrophils exhibit normal LFA-1 dependent adhesion in mouse and man. However, using intravital multiphoton microscopy in cremaster muscles of Mst1-deficient mice, we could show a severe impairment of neutrophil transmigration at the level of basement membrane penetration. This seems to be accompanied by defective mobilization of the integrins VLA3 and VLA6, as well as of neutrophil elastase (NE) to the surface of Mst1-deficient neutrophils. VLA3, VLA6, and NE are discussed as important factors for the successful penetration of the basement membrane during leukocyte recruitment. Taken together and based on our preliminary results, this research proposal is intended to proof our hypothesis that MST1 is a critical regulator of neutrophil basement membrane penetration during the recruitment process identifying MST1 deficiency as the first immunodeficiency disorder in man with a neutrophil basement membrane penetration defect.
炎症期间的白细胞募集是一个重要的免疫学过程,使白细胞能够离开血管内隔室并迁移到炎症组织中。白细胞的募集伴随着一系列的黏附和激活事件,大致可分为白细胞卷曲、白细胞黏附和白细胞移行。一些描述了先天免疫缺陷疾病(F.E.白细胞黏附缺陷I(LAD-I)导致白细胞募集的强烈减少,有利于严重细菌感染的发生。2012年,三个独立的小组(包括我们的合作伙伴Christoph Klein教授,慕尼黑S儿童医院)描述了一种新的免疫缺陷疾病,其特征是哺乳动物不育20-样蛋白激酶1(MST1)基因发生功能丧失突变。患有这种疾病的患者经常表现出反复的细菌和病毒感染,明显的淋巴细胞减少,以及细胞凋亡增加。在相应的小鼠模型(Mst1缺陷小鼠)中,淋巴细胞粘附性严重降低,这是由于含有β2整合素LFA-1的囊泡缺陷动员到淋巴细胞表面所致。目前,缺乏对Mst1缺乏的中性粒细胞(和单核细胞)的黏附特性的研究。因此,我们的研究计划旨在研究MST1缺陷性中性粒细胞在适当的小鼠模型和MST1缺乏症患者中的黏附功能。我们的第一个初步结果令人惊讶地显示,Mst1缺陷的中性粒细胞在小鼠和人身上表现出正常的LFA-1依赖的黏附。然而,在Mst1基因缺陷小鼠的提睾肌中使用活体多光子显微镜,我们可以在基底膜穿透的水平上显示中性粒细胞迁移的严重障碍。这似乎伴随着整合素VLA3和VLA6以及中性粒细胞弹性蛋白酶(NE)在Mst1缺陷的中性粒细胞表面的缺陷动员。VLA3、VLA6和NE被认为是白细胞募集过程中基底膜成功穿透的重要因素。综上所述,基于我们的初步结果,这项研究建议旨在证明我们的假设,即MST1是中性粒细胞基底膜穿透的关键调节因子,在招募过程中将MST1缺陷确定为中性粒细胞基底膜穿透缺陷男性的第一种免疫缺陷疾病。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Professor Dr. Markus Sperandio其他文献
Professor Dr. Markus Sperandio的其他文献
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{{ truncateString('Professor Dr. Markus Sperandio', 18)}}的其他基金
Molekulare Mechanismen der Leukozytenrekrutierung
白细胞募集的分子机制
- 批准号:
5431895 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Research Grants
Endotheliale L-Selektin-Liganden in nicht-lymphoiden Geweben
非淋巴组织中的内皮 L-选择素配体
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5205440 - 财政年份:1999
- 资助金额:
-- - 项目类别:
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