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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 EGFR及其相关的细胞凋亡和细胞生存通路在慢性紫外线照射下皮肤癌的发病机制中起着重要作用。我们以前报道过紫外线辐射诱导EGFR激活。我们的初步研究表明，p38通路的激活与紫外线诱导的细胞凋亡有关，而Akt通路的激活则保护细胞免于死亡。此外，紫外线辐射诱导对细胞生存至关重要的mTOR的激活。虽然紫外线诱发皮肤癌的分子机制仍不清楚，但人们已经寻求了一些方法来预防紫外线辐射。最吸引人的是含有CpG基序的寡核苷酸(或CpG-ODN)的潜在临床应用，它可以很好地激活免疫细胞，并作为抗过敏和癌症疫苗策略的佐剂。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复合体1(TORC1)是CpG-ODN/Akt轴的下游靶点。此外，我们还证明了CpG-ODN对紫外线诱导的细胞死亡具有保护作用。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不清楚。因此，我们制定了三个特定的目标来阐明这些问题：p38如何触发细胞凋亡以响应紫外线辐射？紫外线是如何诱导Akt和mTORC1激活的？CpG-ODN如何防止紫外线诱导的细胞死亡？我们的研究将勾画出紫外线诱导细胞凋亡和CpG-ODN保护紫外线诱导的细胞死亡的新的细胞信号通路。

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.