NFAT Transcription Factors Control the Fate of Keratinocytes and Lymphocytes in Skin Homeostasis and Inflammatory Skin Diseases
NFAT 转录因子控制皮肤稳态和炎症性皮肤病中角质形成细胞和淋巴细胞的命运
基本信息
- 批准号:437826654
- 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:2020
- 资助国家:德国
- 起止时间:2019-12-31 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Skin homeostasis relies on tightly regulated innate and adaptive immune responses. Immunologic dysbalances at the molecular immunological level can promote inflammatory skin diseases, which are often associated with lymphocytic skin infiltration and consecutive alteration of keratinocyte differentiation.The transcription factors of the NFAT family play an important role in these processes, especially by controlling the activity of T lymphocytes. Using NFATc1- and NFATc2-deficient T-cells in an in vitro keratinocyte/T-cell co-culture model we could recently show that these T cells almost completely stop the keratinocytic synthesis of the lymphocyte-attracting chemokines CXCL9 and CXCL10. Furthermore, our ongoing work hints to an unexpected role of NFAT5, a member of the NFAT family, in the differentiation of keratinocytes and epidermal integrity. Among major putative NFAT5-controlled genes are kallikrein 7 (KLK7) and matrix metalloproteinase 3 (MMP3), which promote the differentiation of keratinocytes to corneocytes.Using mouse models of prototypical inflammatory skin diseases (lichenoid dermatitis, atopic eczema) we will investigate the role of NFAT factors in inflammatory processes and pathological keratinocyte differentiation by applying conditional NFATc1 and NFAT5 knockout mice. On the one hand, we want to understand the importance of NFAT factors for the first activation steps of (auto-)antigen-specific lymphocytes in the draining lymph nodes and for T lymphocyte invasion into the skin. On the other hand, we intend to investigate their direct and indirect influence on keratinocyte differentiation under steady-state and inflammatory conditions. The work program includes the use of molecular, cell biological and immunological methods to identify relevant T lymphocyte subpopulations in genetically modified mice and to genome-wide characterize NFAT-regulated gene expression programs in lymphocytes and the epidermis. Findings will be evaluated in parallel by analysis of lesional and non-lasional human skin and circulating lymphocytes from patients with lichen planus and atopic eczema as well as control individuals.Our proposed project will shed more light on the molecular mechanisms controlling human inflammatory skin diseases to specifically tackle NFAT-dependent signaling pathways for novel therapeutic approaches.
皮肤稳态依赖于严格调节的先天性和适应性免疫反应。 分子免疫水平上的免疫失衡可促进炎症性皮肤病的发生,这些炎症性皮肤病通常与皮肤淋巴细胞浸润和角质形成细胞分化的连续改变有关,NFAT家族转录因子在这些过程中起重要作用,尤其是通过控制T淋巴细胞的活性。在体外角质形成细胞/T细胞共培养模型中使用NFATc 1-和NFATc 2-缺陷的T细胞,我们最近可以表明这些T细胞几乎完全停止吸引淋巴细胞的趋化因子CXCL 9和CXCL 10的角质形成细胞合成。此外,我们正在进行的工作暗示了NFAT家族成员NFAT 5在角质形成细胞分化和表皮完整性中的意想不到的作用。其中主要的假定NFAT 5控制的基因是激肽释放酶7(KLK 7)和基质金属蛋白酶3(MMP 3),促进角质形成细胞的分化为corneocytes.Using小鼠模型的典型炎症性皮肤病(苔藓样皮炎,特应性湿疹),我们将调查的作用NFAT因子在炎症过程和病理角质形成细胞分化的应用条件NFATc 1和NFAT 5基因敲除小鼠。一方面,我们希望了解NFAT因子对于引流淋巴结中(自身)抗原特异性淋巴细胞的第一活化步骤和T淋巴细胞侵入皮肤的重要性。另一方面,我们打算调查他们的直接和间接的影响下,稳态和炎症条件下的角质形成细胞分化。该工作计划包括使用分子,细胞生物学和免疫学方法来鉴定转基因小鼠中相关的T淋巴细胞亚群,并在淋巴细胞和表皮中全基因组表征NFAT调节的基因表达程序。研究结果将通过对扁平苔藓和特应性湿疹患者的皮损和非皮损皮肤以及循环淋巴细胞以及对照个体的分析进行平行评估。我们提出的项目将揭示更多控制人类炎症性皮肤病的分子机制,以专门解决NFAT依赖的信号通路的新治疗方法。
项目成果
期刊论文数量(0)
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Professor Dr. Matthias Goebeler其他文献
Professor Dr. Matthias Goebeler的其他文献
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{{ truncateString('Professor Dr. Matthias Goebeler', 18)}}的其他基金
Role of the Transcription Factor NFATc1 in Psoriasis and Psoriasis-like Skin Inflammation
转录因子 NFATc1 在银屑病和银屑病样皮肤炎症中的作用
- 批准号:
327393219 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Research Grants
Intrazelluläre Signalwege der Endothelzellaktivierung und ihre Bedeutung für die inflammatorische Leukozytenrekrutierung
内皮细胞激活的细胞内信号通路及其对炎症白细胞募集的重要性
- 批准号:
5140090 - 财政年份:1998
- 资助金额:
-- - 项目类别:
Research Grants
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