eIF2α-血红素氧合酶1通路在长波紫外线损伤中的机制研究

Ultraviolet A (UVA, 320-400 nm) irradiation causes significant oxidative stress to human skin, leads to inflammation, photoaging, and contributes to skin cancer. UVA also leads to the strong up-regulation of heme oxygenase-1 (HO-1) expression in human dermal skin fibroblasts (FBs) and activates eIF2α(eukaryotic translation initiation factor 2 alpha). Both HO-1 induction and eIF2α activation are cellular response to oxidative stress. It is not clear if eIF2α and downstream factors join with transcription factor Nrf2 (Nuclear factor -erythroid (NF-E2)-related factor2) and Bach1 (BTB and CNC-homology 1) to mediate the induction of HO-1 by UVA irradiation, therefore protect skin against UVA-induced damage,thus contributes to the restoration of cellular redox homeostasis. We've found that the UVA-induced HO-1 levels is correlated with Nrf2 and Bach1 and modulate Nrf2 or Bach1 levels may alter cellular response to UVA irradiation. We hypothesize that eIF2α pathway joins with Nrf2, antagonist with Bach1 to regulate HO-1 expression. We aim to identify eIF2α via downstream activate transcription factor (ATF3 and ATF4), together with Nrf2, to balance with suppressor Bach1 to modulate HO-1 expression. In this study, the biological effects of eIF2α/Nrf2 and Bach1 -HO-1 pathway on UVA induced damage in vitro in FBs as well as in vivo in mice skin will be illustrated. This study may offer guidance to the reduction of photoaging, photodamage as well as effectively using of phototherapy.

长波紫外线UVA损伤机体同时诱导保护性作用分子，但目前尚无突破性发现。UVA照射人体皮肤成纤维细胞FBs诱导血红素氧合酶1(HO-1) 的高表达，与Nrf2及Bach1分别呈正、负相关。我们发现UVA激活翻译起始因子eIF2α,但eIF2α是否参与转录因子Nrf2及Bach1调控HO-1从而对皮肤应激、内环境的稳态起保护作用未知。我们假定eIF2α及下游分子加入Nrf2及Bach1通路调节HO-1表达。本项目拟使用FBs，研究eIF2α及下游分子参与Nrf2及Bach1 调控UVA诱导HO-1表达的机制，明确该通路对UVA所致细胞生物学行为的作用以及动物光老化的影响；阐明eIF2α/Nrf2及Bach1 动态调节HO-1表达的保护作用，为抵御UVA照射皮肤损伤、抗光老化及临床光治疗提供理论基础。

长波紫外线UVA损伤机体同时诱导保护性作用分子如血红素氧合酶1(HO-1)。皮肤细胞中，UVA双次照射诱导HO-1的程度衰减/Refractoriness机制与Nrf2/Bach1相关；UVA 诱导eIF2α磷酸化（eIF2α~P）对HO-1调控激活可能是一种保护机制；抗氧化如乳香酸AKBA可调节Nrf2、Bach1 而改变UVA照射引起的效应：Nrf2激活（通过AKBA/纳米材料包裹）及抑制（鸦胆子苦醇BR）可通过II型解毒酶（尤其HO-1）及NOX1, 炎性因子ILs等改变UVA照射对皮肤细胞损伤的作用。UVA照射与BR协同抑制细胞增殖，通过抑制Nrf2/AKT通路对黑色素瘤起抑制作用。这些均为光损伤机制，光释放药物、临床光疗皮肤疾病提供基础。最后，皮肤原代成纤维细胞中，UVA诱导的衰老模型已建立，与Nrf2、Bach1/HO-1相关性正在探讨。.重要发现：UVA照射皮肤细胞（角质形成细胞及成纤维细胞）导致剪切型血红素氧合酶tHO-1/28 KD增高（请见后），目前正在进行tHO-1与衰老的相关机制研究，为2017年申请NSFC打下基础。 .获国家自然基金2016-2017资助：81573073，25万元，光响应氧化锌负载AKBA防治多形性日光疹的效应及分子机制研究。.已发表高水平学术论文SCI 4篇，另4篇已投出或正在投稿，其中IF> 5的2篇。已培养及联合培养5名博士毕业 (3名高校工作，1名皮肤科研究工作并获国家自然科学基金资助；1名国际学生，已通过学校审批留下做博士后)。培养了5名硕士研究生（2013、14、15、16 年毕业）。 .该项目培育了Molecular Aspects of UVA书籍出版（与Springer 意向签约）；以及Environment/UV-Human-Cell为教育部《分子生物学》全英文课程单元课。