Protecting immune system by modulators of p53 and NF-kB

这一提议涉及一类新的放射性保护剂——由微生物和肿瘤细胞产生的天然产物，它们通过激活细胞内部防御机制和抑制程序性细胞死亡（凋亡）作为宿主生物自然生存策略的一部分而起作用。具体而言，该项目专注于开发源自沙门氏菌鞭毛蛋白和人类TGFbeta2潜伏形式的产品，两者都通过与特定细胞受体（分别为toll样受体5和TGFbeta受体1和2）相互作用，作为nf - kappab激活剂。在前期工作中，我们完成了这两种因子的结构功能优化，并创造了命名的产品，显示出强大的抗凋亡活性。CBLB502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卓越疗效，从而验证了我们的放射防护方法。到目前为止，我们一直在研究致命辐射剂量和辐射损伤急性后果的治疗。该计划的成功使我们现在能够解决我们产品活动的另一个辐射防护方面-

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.