放射损伤后长期性皮肤愈伤能力障碍的表皮干细胞机制研究

Radiotherapy is wildly used in tumor treatment. It is well known that ionizing radiation (IR) can lead to impaired wound healing capability of the irradiated skin, resulting in complication in subsequent surgical treatments. Skin epithelial stem cells(SCs) play key roles in wound healing, but potential long-term impact of IR damage on these SCs are unclear. By analyzing skin samples from post-radiotherapy patients, we found that in the irradiated region, skin epithelial SCs appears to stay in a abnormal steady state that is characterized by simultaneously up-regulated cell proliferation and apoptosis, as well as up-regulated wound healing markers and deregulated Hippo pathway activity. We speculate that IR damaged skin epithelial SCs carry long-term functional defects which contribute to the impaired wounding healing ability of the irradiated skin. To test this hypothesis, we will conduct in-depth analysis of irradiated patient skin samples. From these samples, we will also isolate their skin epithelial SCs for transcriptome analysis and in vitro 2D/3D culture functional analysis. Through these studies, we will systematically elucidate the molecular mechanisms underlying the long-term defect of IR damaged skin SCs, and identify novel therapeutic targets for this difficult-to-treat skin condition.

放疗是恶性肿瘤常用的治疗手段，常导致照射部位皮肤组织长期性的愈伤能力缺陷, 为后续的手术治疗带来并发症风险。表皮干细胞在皮肤愈伤过程中发挥重要作用，但放射性损伤对表皮干细胞的长期影响并不清楚。申请人项目组的前期研究发现，放疗后患者皮肤样品中的表皮干细胞长期处于增殖与凋亡同步上调的异常稳态中，并呈现出异常的Hippo信号通路活性与愈伤相关标记蛋白表达，推测放射损伤后表皮干细胞中存在长期性功能紊乱并导致其愈伤能力缺陷。为了验证以上假设，我们拟对放疗后长时间患者的皮肤样品进行深入分析，并从中分离表皮干细胞以进行全面的转录组分析与体外2D/3D培养模型中的功能分析。通过这些研究，我们将系统性阐明放射损伤后人表皮干细胞长期功能紊乱的分子机制，为放射性皮肤损伤的治疗鉴定新靶点。

放射性皮炎(RD)是因暴露于电离辐射而引起的皮肤损害，是临床肿瘤放疗最常见的并发症之一。除了急性损伤之外，RD还能够导致皮肤上皮组织及其附属器官的长期性病变，包括表皮变薄、永久脱毛、皮脂腺萎缩、愈伤功能障碍等。目前，我们对导致RD长期症状的分子机制仍缺乏了解，临床上也没有特效疗法。在本项目中，我们围绕“电离辐射对皮肤上皮干细胞的长期影响”这一核心科学问题进行了系统性解析，发现了驱动RD长期症状形成的关键分子机制，并开发了多种新型靶向干预技术和候选药物。具体而言，我们首先开创了一套在小鼠体内模拟人类RD长期症状的新技术体系，为RD研究提供了重要模型。随后，我们发现由miR-31-MAPK/ERK信号通路激活导致的皮肤上皮干细胞耗竭是导致RD长期症状的重要分子基础与有效干预靶点。在此基础上，我们开发出了基于经典MAPK/ERK抑制剂“老药新用”的RD防治新技术,为RD治疗提供了极具临床潜力的全新途径。此外，我们还发明了一类通过靶向抑制BCL10来限制NFKB通路过度激活的新型多肽抑制剂，为靶向干预RD相关的皮肤炎症提供了一类新型候选药物。