应用毛发和羽毛模型研究化疗药物损伤正常组织的分子机制

Chemotherapy is currently widely used in treating cancer patients. While blocking tumor growth, chemo-drugs also damage normal proliferating tissues, causing side effects such as hair loss, myelosuppression, gastrointestinal abnormality and bladder cystitis. This is generally believed as a "non-specific killing" effect, a notion not seriously challenged so far. Here we use mouse hair and avian feather as experimental models, combining knock-out mice, whole genome expression profiling, and patient sample analysis to address the molecular mechanism of chemotherapy-induced side effects. We find that down-regulation of Shh signaling plays a critical role in this process. We propose to further investigate: (1) how chemo-drugs down-regulate Shh expression; (2) how Shh down-regulation leads to hair loss; (3) is our finding only limited to a specific drug (cyclophosphamide) induced hair loss, or more generally a mechanism that also true for other chemo-drugs that cause hair loss, or even further, other side effects such as GI tract abnormality and bladder cystitis? and finally, (4) can we find new ways to ameliorate or rescue chemotherapy induced alopecia (CIA) and other damages? Our results will bring in new insights regarding Shh signaling pathway.

化疗是目前治疗癌症最主要的方法之一。化疗药物在抑制肿瘤生长的同时，对一些旺盛生长的正常组织也造成损伤，引起脱发、骨髓抑制、胃肠道功能紊乱、膀胱炎症等副作用。一般认为，这是一种"非特异的杀伤"作用。这一理念至今基本上没有受到严肃的挑战。应用小鼠毛发和鸟类羽毛作为实验模型，综合采用基因敲除小鼠、全基因组表达谱分析，并结合临床病人的样品分析，我们发现在化疗药物损伤正常组织的过程中，Shh信号下调可能起到了关键作用。本计划将继续探讨（1）药物如何引起Shh基因表达下调；（2）Shh信号下调如何导致脱发；（3）我们的发现是否仅仅局限于环磷酰胺一种药物引起的脱发，还是具有普遍的意义，包括其它广泛使用的化疗药物导致的脱发，甚至包括更一般的化疗副作用，如胃肠道反应、膀胱炎症等？（4）最后，根据我们的研究，是否能够找到一些新的方法和手段，以缓解、挽救脱发和其它副作用？本研究将对Shh信号途径产生新的认识。

本实验室的长远目标是以鸟类的羽毛和哺乳动物的毛发和皮肤为模型，（1）探讨其中关于发育、再生和组织构建的基本原理，以及（2）对一些与疾病和治疗相关的实际问题进行研究，力求解决一些与人类健康和疾病息息相关的具体问题，比如毛发再生，皮肤相关疾病，以及肿瘤治疗方面的问题，等等。.在一年期国家自然科学基金项目 31371472 （应用毛发和羽毛模型研究化疗药物损伤正常组织的分子机制）支持下，我们得到了一些阶段性的成果，包括发表SCI 论文两篇：.Wang M, Yue Z*, Paus R, Ramot Y.SIRT2 as a new player in epigenetic programming of keratinocyte differentiation and a candidate tumor suppressor. Exp Dermatol. 2014 Sep;23(9):636-8. （IF 4.1，皮肤病学2级期刊）本文论述了皮肤角蛋白基因的表达调控问题，尤其是Sirt2基因的表观遗传调控作用。.Xie G, Wang H, Yan Z, Cai L, Zhou G, He W, Paus R, Yue Z*.Testing Chemotherapeutic Agents in the Feather Follicle Identifies a Selective Blockade of Cell Proliferation and a Key Role for Sonic Hedgehog Signaling in Chemotherapy-Induced Tissue Damage. J Invest Dermatol. 2014 Sep 18. doi: 10.1038/jid.2014.409. [Epub ahead of print] （IF 6.3，皮肤病学1级期刊）本文提出了化疗药物损伤组织的关键介导因素是Shh信号通路。.另外尚有两篇论文在投稿中。本项目执行情况根据一年期项目的实际进行修改。