Calcineurin signaling in the keratinocyte UVB response

角质形成细胞 UVB 反应中的钙调神经磷酸酶信号传导

• 批准号: 7902146
• 负责人: GIAN-PAOLO DOTTO
• 金额: $ 35.68万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902146
• 关键词: Acute; Apoptosis; Behavior; Biochemical; Biological Assay; Biological Process; Calcineurin; Calcium; Calcium Signaling; Calmodulin; Cell Cycle; Cells; Complement; Differentiation and Growth; Epithelial Cells; Genes; Genetic; Hair; Hair Cells; In Vitro; Inflammatory; Link; Maintenance; Mediator of activation protein; Mus; Notch Signaling Pathway; Play; Protein Serine/Threonine Phosphatase; Protocols documentation; Reaction; Regulation; Research Design; Role; Signal Transduction; Skin; Skin Transplantation; Skin graft; TP53 gene; Testing; Tumorigenicity; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Withdrawal; Work; base; carcinogenesis; cell type; in vitro Assay; in vivo; keratinocyte; ras Oncogene; reconstitution; research study; response; stem cell population; synergism; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Calcineurin (PP2B) is the only known serine/threonine phosphatase under calcium/calmodulin control and a key mediator of intracellular calcium signaling. The biochemical and biological functions of Calcineurin in epithelial cells have been mostly unexplored. In recent work, we have shown that Calcineurin plays a key role in keratinocyte growth/differentiation control and the hair cycle. The present studies are designed to test the hypothesis that Calcineurin plays a similarly important role in the response of keratinocytes to UVB exposure, impinging on intrinsic regulation of these cells as well as their capability to modulate other cell types in the skin. Our approach will be based on a keratinocyte-specific genetic deletion of the Calcineurin B1 gene (CnB1), which is essential for Calcineurin activity in these cells. By a combination of functional and biochemical assays, we will test the further hypothesis that Calcineurin functions in concert with the p53 and Notch signaling pathways in the intrinsic decision of keratinocytes to enter cell cycle withdrawal, apoptosis and/or differentiation. Finally, by a combination of in vivo and in vitro assays, we will test the hypothesis that Calcineurin plays an important role for the long-term consequences of UVB exposure in maintenance of keratinocyte stem cell populations and/or carcinogenesis. Narrative Calcineurin is the only known serine/threonine phosphatase under calcium/calmodulin control and a key mediator of intracellular calcium signaling. The biochemical and biological functions of Calcineurin in epithelial cells have been mostly unexplored. In recent work, we have shown that Calcineurin plays a key role in growth/differentiation control of epidermal cells and the hair cycle. We propose to explore the hypothesis that Calcineurin plays a similarly important role in the acute response of epidermal cells to Ultraviolet Light (UV) exposure, impinging on intrinsic regulation of their behavior as well as their capability to modulate other cell types in the skin. We will further test the hypothesis that Calcineurin plays an essential function in the long term response of epidermal cells to UV exposure, specifically in maintenance of stem cell populations and/or carcinogenesis.

描述（由申请人提供）：钙调神经磷酸酶（PP2B）是唯一已知的受钙/钙调蛋白控制的丝氨酸/苏氨酸磷酸酶，也是细胞内钙信号传导的关键介质。钙调神经磷酸酶在上皮细胞中的生化和生物学功能大多尚未被探索。在最近的工作中，我们表明钙调神经磷酸酶在角质形成细胞生长/分化控制和毛发周期中发挥着关键作用。目前的研究旨在检验以下假设：钙调神经磷酸酶在角质形成细胞对 UVB 照射的反应中发挥着类似重要的作用，影响这些细胞的内在调节以及它们调节皮肤中其他细胞类型的能力。我们的方法将基于钙调神经磷酸酶 B1 基因 (CnB1) 的角质形成细胞特异性遗传删除，该基因对于这些细胞中的钙调神经磷酸酶活性至关重要。通过功能和生化检测的结合，我们将测试进一步的假设，即钙调神经磷酸酶与 p53 和 Notch 信号通路在角质形成细胞进入细胞周期退出、凋亡和/或分化的内在决定中协同作用。最后，通过体内和体外试验的结合，我们将检验以下假设：钙调神经磷酸酶在 UVB 暴露在维持角质形成细胞干细胞群和/或癌发生的长期后果中发挥着重要作用。叙述 钙调神经磷酸酶是唯一已知的受钙/钙调蛋白控制的丝氨酸/苏氨酸磷酸酶，也是细胞内钙信号传导的关键介质。钙调神经磷酸酶在上皮细胞中的生化和生物学功能大多尚未被探索。在最近的工作中，我们表明钙调神经磷酸酶在表皮细胞和毛发周期的生长/分化控制中发挥着关键作用。我们建议探索这样的假设：钙调神经磷酸酶在表皮细胞对紫外线（UV）暴露的急性反应中发挥着类似的重要作用，影响其行为的内在调节以及调节皮肤中其他细胞类型的能力。我们将进一步检验以下假设：钙调神经磷酸酶在表皮细胞对紫外线照射的长期反应中发挥重要作用，特别是在干细胞群的维持和/或致癌作用中。