THE ROLE OF UROKINASE IN LUNG T LYMPHOCYTE RESPONSES
尿激酶在肺 T 淋巴细胞反应中的作用
基本信息
- 批准号:6629002
- 负责人:
- 金额:$ 25.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-02-01 至 2004-01-31
- 项目状态:已结题
- 来源:
- 关键词:Cryptococcus neoformans JAK kinase T cell receptor anergy apoptosis biological signal transduction cellular immunity genetically modified animals helper T lymphocyte interleukin 12 intracellular transport laboratory mouse leukocyte activation /transformation lymphocyte proliferation plasminogen activator receptor receptor binding respiratory infections urokinase
项目摘要
We have demonstrated that uPA is required for effective pulmonary defense against Cryptococcus neoformans (C. neo) infection in vivo. Host defense against C. neo is absolutely T cell dependent. In the absence of uPA, lung accumulation of CD4 cells fails to occur in response to infection, and the uPA minus/minus animals die from disseminated Cryptococcosis. We found that the T cell impairment in the absence of uPA is not specific to C. neo. In vivo, uPA minus/minus mice fail to increase pulmonary CD4 cells in response to P. carinii, and do not clear the infection. We have found that T cell proliferative responses are profoundly impaired in the absence of uPA. In vitro, uPA minus/minus lymphocytes do not undergo antigen-specific proliferation, nor do they proliferate in response to TCR- mediated signals generated by CD3-cross-linking, or by mitogen. Effective host defense to T-cell specific pathogens in vivo; and normal responses in vitro T cell proliferation assays induced by antigen, mitogen, or by CD3-cross-linking, are linked by a common signaling pathway mediated primarily through the TCR-protein kinase cascade, and coupled to co-stimulatory signals delivered by CD28 and CD25. It is our hypothesis that in the absence of uPA, T lymphocyte intracellular signaling via Jak/STAT is diminished leading to inadequate cytokine production and diminished cytokine responsiveness. The lack of Jak/STAT signaling results in blocked T cell activation and proliferation; and T cell unresponsiveness to further TCR-mediated signaling. 1. Localize the biochemical block(s) in T cell signaling cascades. a) Determine if the absence of uPA diminishes TCR- mediated signaling. b) Determine if the absence of uPA diminishes CD28- and CD25-mediated signaling. c) Determine whether uPA activates Jak/STAT signaling in murine T lymphocytes. 2. Determine the functional consequences of aberrant T cell signaling. a) Determine the requirement for uPA in lymphocyte activation as measured by expression of activation antigens, elaboration of cytokines, and responsiveness to IL-12. b) Determine whether the defects in uPA minus/minus lymphocyte signaling result in anergy, cell cycle arrest, or apoptosis. 3. Determine the cellular expression and trafficking of uPA and uPAR during T cell activation and proliferation in vitro. Determine if recombinant uPA can reverse the functional abnormalities in uPA minus/minus lymphocytes.
我们已经证明,uPA是有效的肺部防御体内新型隐球菌(C. neo)感染所必需的。宿主对新冠病毒的防御完全依赖于T细胞。在缺乏uPA的情况下,肺部CD4细胞的积累不能对感染做出反应,uPA阴性/阴性的动物死于播散性隐球菌病。我们发现,在缺乏uPA的情况下,T细胞损伤并不是C. neo特有的。在体内,uPA阴性/阴性小鼠对卡氏疟原虫的反应不能增加肺部CD4细胞,也不能清除感染。我们发现在缺乏uPA的情况下,T细胞的增殖反应严重受损。在体外,uPA负/负淋巴细胞不会发生抗原特异性增殖,也不会响应cd3交联或有丝分裂原产生的TCR介导信号而增殖。体内对t细胞特异性病原体的有效宿主防御在抗原、有丝分裂原或cd3交联诱导的体外T细胞增殖试验中,正常反应是由主要通过tcr -蛋白激酶级联介导的共同信号通路连接的,并与CD28和CD25传递的共刺激信号耦合。我们的假设是,在缺乏uPA的情况下,T淋巴细胞通过Jak/STAT的细胞内信号传导减少,导致细胞因子产生不足和细胞因子反应性降低。缺乏Jak/STAT信号导致T细胞活化和增殖受阻;T细胞对进一步的tcr介导的信号没有反应。1. 定位生化阻滞在T细胞信号级联中的作用。a)确定uPA的缺失是否会减弱TCR介导的信号传导。b)确定uPA的缺失是否会减少CD28和cd25介导的信号传导。c)确定uPA是否激活小鼠T淋巴细胞中的Jak/STAT信号。2. 确定异常T细胞信号传导的功能后果。a)通过活化抗原的表达、细胞因子的表达和对IL-12的反应来确定淋巴细胞活化对uPA的需求。b)确定uPA负/负淋巴细胞信号缺陷是否导致能量、细胞周期阻滞或细胞凋亡。3. 测定体外T细胞活化和增殖过程中uPA和uPAR的细胞表达和运输。确定重组uPA是否能逆转uPA阴性/阴性淋巴细胞的功能异常。
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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MARGARET R GYETKO其他文献
MARGARET R GYETKO的其他文献
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{{ truncateString('MARGARET R GYETKO', 18)}}的其他基金
THE ROLE OF UROKINASE IN LUNG T LYMPHOCYTE RESPONSES
尿激酶在肺 T 淋巴细胞反应中的作用
- 批准号:
6351533 - 财政年份:2000
- 资助金额:
$ 25.21万 - 项目类别:
THE ROLE OF UROKINASE IN LUNG T LYMPHOCYTE RESPONSES
尿激酶在肺 T 淋巴细胞反应中的作用
- 批准号:
6045022 - 财政年份:2000
- 资助金额:
$ 25.21万 - 项目类别:
THE ROLE OF UROKINASE IN LUNG T LYMPHOCYTE RESPONSES
尿激酶在肺 T 淋巴细胞反应中的作用
- 批准号:
6498967 - 财政年份:2000
- 资助金额:
$ 25.21万 - 项目类别: