Specialized Pro-resolving Mediators (SPMs) & scar tissue formation after cleft-lip surgical repair

项目摘要/摘要 唇裂伴或不伴腭裂是最常见的先天性头部和唇裂畸形。 第三个最常见的出生缺陷。唇裂对儿童和家庭生活质量的影响是显而易见的。 严重影响儿童的外表、言语、听力、成长、心理社会福祉和社会融合。 手术修复嘴唇是唯一的治疗方法，通常在生命的第一年进行。然而， 增生性瘢痕(HTS)是一种常见的术后并发症，它损害软组织的形态、功能和功能。 儿童时期需要动动和多次唇部整形手术才能达到最佳的美学效果。 和功能。失控和持续的炎症在组织损伤、组织疤痕形成和 纤维化症。迫切需要新的治疗方案来帮助容易形成疤痕组织的患者。 在唇部修复和整形手术后。这项提议的目的是评估一种新的方法来促进 创面愈合和限制疤痕形成基于内源性的专门化促分解脂质介体(SPM)， 被称为Resolvins。最重要的假设是，局部应用解毒素将使肥大最小化。 通过促进炎症消退来促进唇裂修复手术后的疤痕形成。这个问题将会得到解决 分两个阶段：将在动物模型中确定分解素在预防嘴唇瘢痕形成中的作用。 由最初的人体研究降低，这将为未来的人类临床应用产生假设。具体的 目的是：1)描述唇裂修复后增生性瘢痕的炎性/脂质介质的特征。 在FDA批准的动物模型中配对；1)使用兔子模型，我们将确定井的影响 针对瘢痕形成和炎症/脂质介质的专门化促分解脂介质(RvE1)- TORS在唇裂修复术后伤口愈合中的作用；2)表征人类炎症/脂质介质的特征 在接受唇裂修复手术的患者中，唇裂伤口渗出物的发生率及其与疤痕形成的相关性。 这些目标也为Evangelos Papathanasiou博士提供了指导培训经验，他是一名有才华的 初级牙医-在免疫学和口腔生物学方面有很强背景的科学家。帕帕塔纳修博士的职业生涯 目标是整合药物开发、组织工程和临床研究的进展，以开发 口腔和颅面组织再生的新生物工程方法和发现新的治疗方法- 口腔疾病治疗用药。帕帕塔纳修博士和他的导师卡罗尔·安·特罗特曼博士和托马斯·范博士 Dyke组建了一支经验丰富的合作者团队，拥有积极资助的研究项目和 致力于他的成功，并确保一个最佳的培训和研究环境和成功 拟议研究的结果。这一K08奖项的预期结果是帮助帕帕塔纳西奥博士 为成为临床转化牙科研究和独立科学家的职业生涯奠定坚实的基础 领导未来新型内源性专门化促分解脂介体的人体临床试验，以加速- 促进伤口愈合，最大限度减少纤维化和疤痕。

PROJECT ABSTRACT/SUMMARY Cleft lip with or without cleft palate is the most common congenital malformation of the head and the third most common birth defect. The impact of cleft lip on quality of life for the child and the family can be se- vere, affecting the child's appearance, speech, hearing, growth, psychosocial well-being and social integration. Surgical repair of the lip is the only treatment and is usually performed during the first year of life. However, hypertrophic scar (HTS) formation is a frequent postoperative complication that impairs soft tissue form, func- tion or movement and multiple lip revision surgeries are required throughout childhood for optimum esthetics and function. Uncontrolled and prolonged inflammation plays a major role in tissue injury, tissue scarring, and fibrosis. There is a critical need for new therapeutic regimens to help patients prone to scar tissue formation after lip repair and revision surgeries. The objective of this proposal is to evaluate a new approach to promote wound healing and limit scarring based on endogenous specialized pro-resolving lipid mediators (SPMs), termed Resolvins. The overarching hypothesis is that resolvins applied topically will minimize hypertrophic scarring after cleft lip repair surgery by promoting resolution of inflammation. The problem will be approached in two phases: the actions of resolvins in prevention of lip scarring will be determined in an animal model, fol- lowed by initial human studies that will generate hypotheses for future human clinical application. The specific aims are: 1a) Characterize the inflammatory/lipid mediator profile of hypertrophic scars after cleft lip defect re- pair in an FDA approved animal model; 1b) Using the rabbit model, we will determine the impact of a well characterized specialized pro-resolving lipid mediator (RvE1) on scar formation and inflammatory/lipid media- tors in wound healing after cleft lip defect repair; 2) Characterize the human inflammatory/lipid mediator profile of cleft lip wound exudate and correlate it with scarring in patients undergoing cleft lip repair surgery. These aims also provide a mentored training experience for Dr. Evangelos Papathanasiou, a talented junior dentist-scientist with a strong background in Immunology and Oral Biology. Dr. Papathanasiou's career goal is to integrate advances in drug development, tissue engineering and clinical research in order to develop new bio-engineered approaches for the regeneration of oral and craniofacial tissues and discover novel treat- ments for oral diseases. Dr. Papathanasiou with his mentors, Dr. Carroll Ann Trotman and Dr. Thomas Van Dyke, has assembled a team of highly experienced collaborators with active funded research programs and with commitment to his success, and to ensure an optimal training and research environment and successful outcomes of the proposed research. The expected outcome of this K08 award is to help Dr. Papathanasiou build a strong foundation for a career as an independent scientist in Clinical Translational Dental Research and to lead future human clinical trials of novel endogenous specialized pro-resolving lipid mediators for accelerat- ing wound healing and minimizing fibrosis and scarring.