MECHANISMS OF CPG-ODN'S PROTECTION AGAINST UV-INDUCED CELL DEATH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 表皮生长因子受体及其相关的细胞凋亡和细胞存活途径在慢性紫外线照射皮肤癌的发病过程中起重要作用。我们之前报道过紫外线辐射会诱导EGFR激活。我们的初步研究表明，p38通路的激活负责紫外线诱导的细胞凋亡，而Akt通路的激活保护细胞免于死亡。此外，UV辐射诱导对细胞存活至关重要的mTOR的活化。虽然紫外线诱导的皮肤癌的分子机制仍然没有得到很好的理解，一些方法正在寻求保护免受紫外线辐射。其中最具吸引力的是含CpG基序的寡脱氧核苷酸（或CpG-ODNs），它具有激活免疫细胞的功能，可作为抗过敏和抗肿瘤疫苗的佐剂。我们以前的研究已经证明CpG-ODN激活Akt。我们的初步数据表明mTOR复合物1（TORC 1）是CpG-ODN/Akt轴的下游靶点。此外，我们发现CpG-ODN可以防止紫外线诱导的细胞死亡。然而，紫外线激活细胞凋亡和存活的分子机制以及CpG-ODN的保护作用在很大程度上仍然未知。因此，我们制定了三个具体的目标来阐明这些问题：p38如何触发细胞凋亡，在响应紫外线辐射？紫外线如何诱导Akt和mTORC 1激活？CpG-ODN如何防止紫外线诱导的细胞死亡？我们的研究将描绘新的细胞信号通路，通过紫外线诱导细胞凋亡和CpG-ODN保护对紫外线诱导的细胞死亡。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. EGFR and its related cell apoptosis and cell survival pathways play an important role in the progress of pathogenesis of skin cancer upon chronic UV radiation. We previously reported that UV radiation induces EGFR activation. Our preliminary studies suggest that activation of p38 pathway is responsible for UV-induced cell apoptosis, whereas activation of Akt pathway protects cells from death. Further, UV radiation induces activation of mTOR that is critical for cell survival. Although the molecular mechanisms of UV-induced skin cancers are still not well understood, a number of approaches are sought to protect against UV radiation. The most attractive one is the potentially clinical usage of oligodeoxynucleotides containing CpG motif (or CpG-ODNs), which are well equipped to activate immune cells and function as adjuvants for vaccine strategy against allergy and cancer. Our previous studies have demonstrated that CpG-ODN activates Akt. Our preliminary data suggests that mTOR complex 1 (TORC1) is a downstream target of CpG-ODN/Akt axis. Further, we show that CpG-ODN protects against UV-induced cell death. Nevertheless, the molecular mechanisms underlying the activation of cell apoptosis and survival by UV and the protective effect of CpG-ODN are still largely unknown. Thus, we have formulated three specific aims to elucidate these issues: How does p38 trigger apoptosis in response to UV radiation? How does UV induce Akt and mTORC1 activation? How does CpG-ODN protect against UV-induced cell death? Our study will delineate novel cell signaling pathways through which UV induces apoptosis and CpG-ODN protects against UV-induced cell death.