Molecular mechanisms of pulsed dye laser combined with topical rapamycin for port

描述（由申请人提供）：鲜红斑痣（PWS）是一种先天性、进行性人类皮肤血管畸形。在美国，大约有120万人有PWS胎记。目前，所有PWS都是使用脉冲染料激光（PDL）治疗的。然而，PWS反应仍然是不可预测的，只有不到10%的患者在PDL后PWS完全消退。此外，由于PWS血管的重建和再灌注，PDL治疗后PWS可复发。治疗抵抗的原因仍然不完全清楚。PWS治疗结果不足是一个临床上重要的问题，迫切需要解决。我们的中心假设是：PDL治疗诱导的血管生成途径的激活是导致PWS血管重建和再灌注的关键因素之一。因此，与单独PDL治疗相比，PDL与血管生成途径抑制剂如雷帕霉素（RPM）联合给药可能潜在地改善PWS病变变白，从而导致更好的治疗结果。该策略（PDL+RPM）的科学原理是PDL用于诱导PWS血管损伤，而RPM局部给药可抑制激光照射后PWS血管的重建和再灌注。拟议的研究将集中在针对临床障碍，似乎减少PWS激光治疗的结果，即重建和再灌注PWS血管后PDL治疗。本文提出了一系列药理学、分子和生物化学方法来支持这种治疗PWS的新方法：（1）新开发的RPM局部制剂的安全性和有效性评价以及药代动力学;（2）RPM介导的对PDL诱导的血管生成途径的抑制的时间过程;（3）完整PWS和不同激光及RPM治疗后病变组织的全基因转录谱，试图揭示PWS发生和发展的分子机制。我们希望这些研究将促进我们对PWS分子病理生理学的理解，并改善PDL治疗的反应。

DESCRIPTION (provided by applicant): Port Wine Stain (PWS) is a congenital, progressive vascular malformation of human skin. Approximately 1,200,000 individuals in the United States have PWS birthmarks. Presently, all PWS are treated using the pulsed dye laser (PDL). However, PWS response remains unpredictable with less than 10% of patients achieving complete fading of their PWS after PDL. Moreover, PWS can recur after PDL therapy due to reformation and reperfusion of PWS blood vessels. The reasons for treatment resistance remains incompletely understood. Inadequate PWS therapeutic outcome is a clinically significant problem that urgently requires a solution. Our central hypothesis in this research proposal is: 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. The scientific rationale for this strategy (PDL+RPM) is that PDL is used to induce PWS blood vessel injury while topical administration of RPM can inhibit reformation and reperfusion of PWS blood vessels after laser exposure. The proposed research will focus on targeting the clinical barrier that appears to diminish PWS laser therapeutic outcome, namely reformation and reperfusion of PWS blood vessels after PDL treatment. A series of pharmacological, molecular and biochemical approaches are proposed herein to support this novel approach for PWS treatment: (1) safety and efficacy evaluations and pharmacokinetics of newly developed topical formulations of RPM; (2) the time course of RPM-mediated inhibition on angiogenesis pathways induced by PDL; (3) whole-transcript profiles from intact PWS and lesions after various laser and RPM treatments in an attempt to reveal the molecular mechanisms underlying origination and development of PWS. We expect the proposed studies will advance our understanding of molecular pathophysiology of PWS and improve response to PDL treatment.