坦罗莫司抑制脉冲染料激光干预后血管再生和再灌注的机制

Port Wine Stain (PWS) is a congenital, progressive vascular malformation of human skin,which presents from birth and heavily affects the physical and mental health of the patients. Currently, The pulsed dye laser (PDL) is the golden standard of the treatment of PWS.However, PWS response remains unpredictable and incomplete,with less than 20% of patients achieving complete fading of lesions even after many times treatment with PDL.The reasons for treatment resistance remains poorly understood, and it may largely due to the reformation and reperfusion of PWS blood vessels after PDL intervention. Our recent preliminary study illuminated that the activation of angiogenesis pathways induced by PDL therapy is one of the crucial factors that causes the reformation and reperfusion of PWS blood vessels. Therefore, PDL combined with administration of angiogenesis pathways' inhibitors, such as rapamycin (RPM), may potentially improve PWS lesion blanching and thus lead to a better therapeutic outcome as compared to PDL treatment alone. .Based on our preliminary study, in this proposal we focus on temsirolimus (TEM,CCI779),a derivative of rapamycime and a target inhibitor of mTOR kinase: (1)whole-transcript profiles analysis after various laser interventions in an attempt to reveal the molecular mechanisms underlying origination and development of PWS. (2)the potential mechanism of TEM in inhibition of the reformation and reperfusion of blood vessles after PDL intervention;(3)safety,efficacy evaluations and pharmacokinetics of newly developed topical formulations of TEM;and the promiton approaches to the transdermal delivery of TEM. We expect the proposed studies will advance our understanding of molecular pathophysiology of PWS and improve response to PDL treatment.

鲜红斑痣是临床常见的先天性皮肤毛细血管畸形，多发于面颈部，严重影响患者的身心健康，目前脉冲染料激光是治疗的金标准，但治愈率低于20%。影响疗效的主要原因在于激光破坏血管的同时，启动了血管再生和再灌注通路，致使血管很快再生和再通，因而抑制血管再生和再灌注是提高激光疗效的关键。课题组前期研究发现雷帕霉素可以抑制激光治疗所致的血管再生和再灌注，显著提高疗效，本研究拟在既往研究基础上，基于水溶性更好的雷帕霉素衍生物-靶向性mTOR激酶抑制剂坦罗莫司进行以下研究：（1）脉冲染料激光治疗鲜红斑痣后所致的血管再生和再灌注的分子机制和生理过程；（2）坦罗莫司抑制激光干预鲜红斑痣所致的血管再生和再灌注的机制；（3）外用坦罗莫司安全性有效性、透皮吸收情况和在真皮内的代谢情况，以及促其通透真皮的措施。通过这些基础研究为临床鲜红斑痣患者激光联合应用坦罗莫司奠定理论基础，从而显著提高鲜红斑痣疗效，为患者造福。

鲜红斑痣是临床常见的先天性皮肤毛细血管畸形，多发于面颈部，严重影响患者的身心健康，目前脉冲染料激光是治疗的金标准，但治愈率低于20%。影响疗效的主要原因在于激光破坏血管的同时，启动了血管再生和再灌注通路，致使血管很快再生和再通，因而抑制血管再生和再灌注是提高激光疗效的关键。课题组前期研究发现雷帕霉素可以抑制激光治疗所致的血管再生和再灌注，显著提高疗效，本研究在既往研究基础上，基于水溶性更好的雷帕霉素衍生物-靶向性mTOR激酶抑制剂坦罗莫司进行了以下研究：（1）探讨基于各种激酶的鲜红斑痣的发生、发展分子机制；（2）坦罗莫司外用剂型的制备、测试，及其抑制激光干预鲜红斑痣所致的血管再生和再灌注的机制；（3）总结了15年的鲜红斑痣患者数据，并进行随访，统计大样本数据下的治愈率、疗效影响因素和复发情况分析；研究595nm脉冲染料和点阵激光联合治疗顽固性鲜红斑痣的疗效。通过这些基础研究为临床鲜红斑痣患者提高疗效奠定基础，更好的为鲜红斑痣患者服务。

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