Signal Transduction Pathways In The Eye Of Transgenic Mi

转基因Mi眼中的信号转导途径

• 批准号: 6826530
• 负责人: ANA B CHEPELINSKY
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6826530
• 关键词: biological signal transduction; cell differentiation; cysteine endopeptidases; developmental genetics; disease /disorder model; enzyme activity; eye; eye neoplasms; gene expression; gene therapy; genetically modified animals; interferon gamma; laboratory mouse; laboratory rat; lens; model design /development; neoplasm /cancer remission /regression; neoplastic process; oncogenes; transcription factor; tumor antigens; tumor suppressor genes; tumor suppressor proteins

In collaborative studies with Dr. Charles Egwuagu (Laboratory of Immunology, NEI) we have been studying the JAK/STAT signaling pathway in the lens. This collaboration resulted in the development of transgenic mice and rats with constitutive expression of gamma interferon in their eyes, which became useful animal models for the study of experimental autoimmune uveitis and anterior uveitis. This ongoing collaboration allowed us to study how constitutive expression of gamma interferon and its induction and activation of gamma interferon-inducible transcription factors in the eye altered the developmental fate of cells destined to become lens fiber cells by altering the pattern of lens gene expression.We found that the expression of the members of the interferon regulatory factors (IRFs) family of transcription factors is not only activated in the gamma interferon transgenic mice, but it is also expressed in the normal lens. Our data indicates that expression of IRF transcription factors is spatially regulated in the lens and that distinct IRFs may contribute to differential gene regulation in the epithelia and fiber compartment of the lens. These findings have important implications for understanding signal transduction pathways in the lens. In another collaborative project with Dr. Charles Egwuagu we generated double transgenic mice expressing gamma interferon (IFN gamma) and the oncogenic SV40 large T antigen (TAg) in the lens. Interferon gamma (IFN gamma) is an anti-neoplastic cytokine used in the treatment of some malignant diseases. However, its use is limited by undesirable side effects resulting from its pleiotropic activities. In this study, we induced lens neoplasia in transgenic mice by targeting expression of SV40 T Antigen (TAg) to the lens and demonstrate complete regression of the tumor by simultaneously expression of IFN gamma in the lens. We show that the neoplastic phenotype is rescued by non-immunological mechanisms mediated by: (I) enhanced expression of IFN gamma-inducible tumor suppressors, IRF-1 and ICSBP; (II) activation of caspase 1, p53 and IFN gamma-dependent apoptosis; (III) inhibition of TAg interactions either with p53 or retinoblastoma protein; (IV) induction of enhanced expression of growth inhibitory proteins, p21WAF1 and p27, by IRF-1 and ICSBP. These results suggest the potential of exploiting the tumor suppressive activities of IRF-1 and ICSBP to provide therapeutic benefits of IFN gamma without its associated adverse effects.

在与Charles Egwuagu博士（NEI免疫学实验室）的合作研究中，我们一直在研究镜头中的JAK/STAT信号通路。这种合作导致了转基因小鼠和大鼠的发展，其眼睛中伽马干扰素的本构表达，这成为研究实验性自身免疫性葡萄膜炎和前葡萄膜炎的有用动物模型。 This ongoing collaboration allowed us to study how constitutive expression of gamma interferon and its induction and activation of gamma interferon-inducible transcription factors in the eye altered the developmental fate of cells destined to become lens fiber cells by altering the pattern of lens gene expression.We found that the expression of the members of the interferon regulatory factors (IRFs) family of transcription factors is not only activated in the gamma interferon transgenic小鼠，但也在正常镜头中表达。我们的数据表明，IRF转录因子的表达在晶状体中受到空间调节，并且不同的IRF可能有助于晶状体上皮和纤维室中的差异基因调节。这些发现对于理解镜头中的信号转导途径具有重要意义。 在与Charles Egwuagu博士的另一个合作项目中，我们在镜头中产生了双重转基因小鼠（IFN Gamma）和致癌SV40大T抗原（TAG）。干扰素伽马（IFN Gamma）是一种用于治疗某些恶性疾病的抗肿瘤细胞因子。但是，它的使用受到其多效活动导致的不良副作用的限制。在这项研究中，我们通过将SV40 T抗原（TAG）的表达靶向透镜来诱导转基因小鼠中的晶状体肿瘤，并通过同时在镜头中表达IFN Gamma来证明肿瘤的完全回归。我们表明，肿瘤表型是通过以下介导的非免疫机制挽救的：（i）增强IFNγ-诱导肿瘤抑制器，IRF-1和ICSBP的表达； （ii）caspase 1，p53和IFNγ依赖性凋亡的激活； （iii）抑制与p53或视网膜细胞瘤蛋白的TAG相互作用； （iv）IRF-1和ICSBP诱导了增强生长抑制蛋白P21WAF1和P27的表达。这些结果表明，利用IRF-1和ICSBP的肿瘤抑制活性以提供IFN Gamma的治疗益处而没有其相关的不良反应的可能性。