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

描述（由申请人提供）：葡萄酒色斑（PWS）是一种先天性进行性皮肤血管畸形。在美国大约有120万人有PWS胎记。目前，所有PWS均采用脉冲染料激光（PDL）治疗。然而，PWS反应仍然不可预测，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，PWS可在PDL治疗后复发。治疗耐药的原因仍不完全清楚。PWS治疗效果不足是一个迫切需要解决的临床重大问题。本研究方案的中心假设是：PDL治疗诱导的血管生成通路的激活是导致PWS血管重构和再灌注的关键因素之一。因此，与单独使用PDL相比，PDL联合使用血管生成途径抑制剂，如雷帕霉素（RPM），可能会潜在地改善PWS病变的变白，从而获得更好的治疗结果。该策略（PDL+RPM）的科学原理是PDL用于诱导PWS血管损伤，而局部给药RPM可抑制激光照射后PWS血管的改造和再灌注。拟开展的研究将重点针对可能降低PWS激光治疗效果的临床障碍，即PWS治疗后PWS血管的改造和再灌注。本文提出了一系列的药理学、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外用制剂的安全性、有效性评估和药代动力学；(2) PDL诱导的rpm介导的血管生成途径抑制的时间过程；(3)完整PWS和病变经过各种激光和RPM治疗后的全转录谱，试图揭示PWS发生和发展的分子机制。我们期望所提出的研究将促进我们对PWS分子病理生理的理解，并提高对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.