Study of gamma interferon agonists/mimetics

描述(由申请人提供)：干扰素(IFNGamma)是调节健康所必需的功能的基本细胞因子，特别是通过或维持通过CD4T辅助细胞(Th1)细胞的功能。此外，IFNGamma还具有直接的抗病毒和抗细胞(抗肿瘤)活性。因此，干扰素-γ模拟物的开发对感染性疾病和癌症的免疫治疗具有重要意义。下面列出的具体目标直接测试这种模拟物的合理开发以及它们在调节IFNGamma活动中的使用。 1.基于序列和结构相似性合成具有生物活性的干扰素-γC端肽模拟物。 2.比较了几种细胞内给药方法，包括化学修饰和分子表达系统的使用。 3.从JAK/STAT的激活、抑癌基因p21WAF/CIP的上调、neu/HER-2原癌基因的下调来确定IFN-γ多肽模拟物在肿瘤细胞中的信号功能。 4.测定干扰素的细胞功能。在抗病毒活性、抗细胞(抗肿瘤)活性和上调MHC II类分子方面的多肽模拟物。 5.检测干扰素-γ模拟肽在病毒感染和肿瘤小鼠模型中的生物活性。

DESCRIPTION (provided by applicant): Gamma interferon (IFNgamma) is an essential cytokine for mediation of functions that are obligatory for good health, particularly that mediated through or maintained through CD4 T helper1 (Th1) cells. Further, IFNgamma possesses direct antiviral and anticellular (antitumor) activity. Thus, the development of IFNgamma mimetics has important implications for immune therapy in infectious diseases and cancer. The Specific Aims listed below directly test both the rational development of such mimetics as well as their use in the mediation of IFNgamma activity. 1. Synthesis of IFNgamma peptide mimetics based on sequence and structural similarity to biologically active IFNgamma C-terminal peptides. 2. Compare several methods for delivery of IFNgamma peptides intracellularly, including chemical modification and use of molecular expression systems. 3. Determine signaling function of IFNgamma peptide mimetics in terms of JAK/STAT activation, upregulation of tumor suppressor gene p21WAF/CIP, and down regulation of neu/HER-2protooncogene in cancer cells. 4. Determine cellular function of IFN? peptide mimetics in terms of antiviral activity, anticellular (antitumor) activity, and upregulation of MHC class II molecules. 5. Determine biological activity of IFNgamma mimetic peptides in mouse models of virus infection and cancer.