Protecting immune system by modulators of p53 and NF-kB

通过 p53 和 NF-kB 调节剂保护免疫系统

• 批准号: 6998623
• 负责人: ANDREI V GUDKOV
• 金额: $ 150万
• 依托单位: CLEVELAND BIOLABS, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6998623
• 关键词: Macaca mulatta; Salmonella typhimurium; androgens; apoptosis; biotechnology; biotherapeutic agent; bone marrow transplantation; disease /disorder model; drug carcinogenesis; drug screening /evaluation; fibroblast growth factor; flagellin; gamma radiation; hematopoiesis; immune system; immunomodulators; immunopharmacology; laboratory mouse; nonhuman therapy evaluation; nuclear factor kappa beta; p53 gene /protein; radiation carcinogenesis; radiation immunosuppression; radioprotective agents; transforming growth factors

This proposal deals with a new class of radioprotectors - natural products generated by microbes and tumor cells that act by activating internal cellular mechanisms of defense and inhibiting programmed cell death (apoptosis) as part of natural survival strategy in the host organism. Specifically, it is focused on development of the product originating from flagellin of Salmonella and latent form of human TGFbeta2, both acting as NF-kappaB-activating agents through interaction with specific cellular receptors (toll-like receptor 5 and TGFbeta receptors 1 and 2, respectively). During our preliminary work, we have completed structure-functional optimization of both factors and created products named, which demonstrated powerful anti-apoptotic activity. CBLB502 has been thoroughly characterized in vivo and showed outstanding efficacy against hematopoietic and gastro-intestinal radiation syndromes, thus validating our approach to radioprotection. So far we have been working with lethal radiation doses and treatment of acute consequences of radiation injury. The success of this program allows us now to address another radioprotective aspect of activity of our products - protection of the immune system - and to evaluate the perspectives of their use for this indication. The study involves: (i) thorough characterization of protective effect of both products on different compartments of immune system (adaptive, innate immunity and stromal components), (ii) evaluation of safety of CBLB502 and CBLB102 by estimation of their effect on radiation-induced carcinogenesis and (iii) testing their protective effect in non-human primates as an essential and final step before full-scale program of development of at least one of the tested compounds into radioprotecting drug.

该提案涉及一类新的辐射防护剂-由微生物和肿瘤细胞产生的天然产物，其通过激活内部细胞防御机制和抑制程序性细胞死亡（细胞凋亡）来发挥作用，作为宿主生物体中自然生存策略的一部分。具体而言，其重点是开发源自沙门氏菌鞭毛蛋白和人TGF β 2潜伏形式的产品，两者均通过与特定细胞受体（分别为toll样受体5和TGF β受体1和2）相互作用而充当NF-κ B激活剂。在我们的前期工作中，我们已经完成了两个因子的结构-功能优化，并创建了命名为的产品，其表现出强大的抗凋亡活性。CBLB 502已经在体内进行了彻底的表征，并显示出对造血和胃肠道辐射综合征的出色功效，从而验证了我们的辐射防护方法。到目前为止，我们一直在研究致命的辐射剂量和治疗辐射损伤的急性后果。该计划的成功使我们现在能够解决我们产品的另一个辐射防护方面的活动- 保护免疫系统-并评估其用于该适应症的前景。该研究涉及：（i）彻底分析两种产品对免疫系统不同部分的保护作用（适应性、先天免疫和基质成分），（ii）通过估计CBLB 502和CBLB 102对辐射诱导致癌作用的影响来评估其安全性，以及（iii）测试其在非人灵长类动物中的保护作用，作为全面研究之前的必要和最后一步-将至少一种测试化合物开发成放射防护药物的规模计划。