Protecting immune system by modulators of p53 and NF-kB

这项提案涉及一类新的辐射防护剂--微生物和肿瘤细胞产生的天然产物，作为宿主生物体自然生存策略的一部分，它们通过激活内部细胞防御机制和抑制程序性细胞死亡(凋亡)来发挥作用。具体地说，它侧重于来自沙门氏菌鞭毛蛋白和人TGFbeta2潜伏期产物的开发，两者都通过与特定的细胞受体(Toll样受体5和TGFbeta受体1和2)相互作用而作为核因子-kappaB激活剂。在我们的前期工作中，我们完成了这两个因子的结构-功能优化，并创造了命名的产品，显示了强大的抗细胞凋亡活性。CBLB502已经在体内得到了彻底的表征，并对造血和胃肠道辐射综合征表现出了突出的疗效，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辐射剂量和治疗辐射损伤的急性后果。这一计划的成功使我们现在可以解决我们产品活动的另一个辐射防护方面- 保护免疫系统--并评估其用于这一适应症的前景。这项研究涉及：(I)对两个产品对免疫系统不同部分(适应性、先天免疫和基质成分)的保护作用进行全面表征，(Ii)通过评估CBLB502和CBLB102对辐射致癌的影响来评估它们的安全性，以及(Iii)测试它们在非人类灵长类动物中的保护效果，这是将至少一种被测试化合物开发为辐射防护药物的全面计划之前的必要和最后一步。

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.