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: 6672729
• 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/6672729
• 关键词: biological signal transduction; cell differentiation; cysteine endopeptidases; developmental genetics; disease /disorder model; enzyme activity; eye; eye neoplasms; gene expression; genetically modified animals; interferon gamma; iridocyclitis; laboratory mouse; laboratory rat; lens; model design /development; neoplasm /cancer remission /regression; neoplastic process; oncogenes; transcription factor; tumor suppressor genes; tumor suppressor proteins; uveitis

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 collaboration with Dr. Charles Egwuagu we developed double transgenic mice expressing gamma interferon and the oncogenic SV40 large T antigen in the lens. Our results showed that in the double transgenic mice, there is a progressive regression of the lens tumor, resulting in complete tumor regression in the adult double transgenic mice. We showed that the anti-tumor effects are not mediated by immunological effector cells. Instead, the rescue of the neoplastic phenotype is mediated in part by enhanced expression of the IFN gamma-inducible tumor suppressors IRF-1 and ICSBP, activation of caspase-1 (or ICE, interleukin-1b-converting enzyme) and IFN gamma-dependent apoptosis. These double transgenic mice are useful animal models for the study of the possible clinical uses of IRFs for tumor regression therapy.

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博士的另一次合作中，我们开发了表达伽玛干扰素和镜头中的致癌SV40大T抗原的双转基因小鼠。我们的结果表明，在双转基因小鼠中，晶状体肿瘤进行了逐渐消退，导致成年双转基因小鼠的肿瘤完全消退。我们表明，抗肿瘤作用不是由免疫效应细胞介导的。取而代之的是，通过增强IFNγ诱导肿瘤抑制剂IRF-1和ICSBP的表达，caspase-1的激活（或ICE，iCE，interleukin-1b转化酶）和IFNγ依赖性的凋亡。这些双转基因小鼠是有用的动物模型，用于研究IRF在肿瘤回归疗法中可能的临床用途。