Novel Mechanisms of Regenerative Fetal Wound Repair by IL-10

描述（由申请人提供）：这个新的研究者提案描述了一个5年的培训计划，以发展儿科和胎儿外科的外科科学家职业生涯。在完成医学博士学位后，这位研究者在成人和儿科普外科方面接受了9年的培训，并获得了这两个领域的委员会认证。这段时间包括在费城儿童医院和辛辛那提儿童医院医疗中心（CCHMC）的Timothy Crombleholme的指导下进行近3年的研究。这位新研究者的主要工作重点是胎儿再生伤口愈合反应。他目前是辛辛那提儿童医院医学中心儿科和胎儿外科的助理教授。他的职业目标是利用这个K08奖来支持他发展成为一名高技能科学家的承诺，并长期过渡到一名成功的、独立的、nih资助的外科医生。CCHMC在促进和支持青年科学家事业方面有着悠久的历史。该机构保证申请人有75%的保护时间致力于他的研究工作。在外科，他是20名普通外科医生之一，并且有很强的部门优先研究和充足的资源来实现这一目标。除了时间承诺外，该机构还为申请人提供了慷慨的启动资金一揽子计划，包括实验室空间，研究资金和5年的辅助支持。此外，自2009年9月开始担任教职以来，该候选人获得了竞争激烈的宝洁学者奖（Procter Scholar Award），该奖项提供了大量额外的工资支持，并获得了KL2奖学金，该奖学金提供了研究资金，并成立了一个严格的监督委员会来监督他在本学年的进展。职业发展计划的基石是一个堪称典范的科学咨询委员会。这四位科学家来自不同的背景，但之前在小组内存在合作关系。每位成员都被认为是各自领域的国际权威，更重要的是，他们在支持年轻科学家和提供有效指导方面有着长期的记录。此外，候选人在与委员会密切协商后，概述了一个教育计划，包括额外的课程，每周实验室会议，全国会议和有组织的研究计划，以完成他的培训。本研究旨在探讨胎儿再生表型的潜在机制。申请人先前检查了IL-10在胎儿伤口愈合反应中的作用，以及通过炎症反应的衰减在产后组织中再现胎儿状态。他的新重点是研究IL- 10介导的细胞外基质（ECM）在胎儿再生表型中的调节作用。申请人提出了一个新的假设，提出IL-10可以通过stat3依赖机制导致真皮成纤维细胞形成再生的细胞周围基质。这种免疫调节剂调节ECM的概念是非常创新的。在检验这一假设时，概述了三个目标。目的1是在细胞水平上确定IL-10对胎儿成纤维细胞表型的重要性，然后确定IL-10是否可以在成人成纤维细胞中再现胎儿状态。目的2阐明stat3介导的成纤维细胞中IL-10的胞内信号转导。Aim 3是对IL-10在再生表型中的作用是STAT3和HAS1介导的假设的体内验证。这三个目标的完成将确保对“胎儿无疤痕伤口愈合”的潜在机制有更清晰的理解，并且可以确定任何以过度纤维增生为特征的疾病的治疗靶点。最后，在5年的资助期内所学到的几项新技术和新概念将有助于申请人的科学训练，从而为他未来的科学生涯提供新的工具和假设。总之，这项研究和训练计划旨在了解胎儿再生反应与伤口愈合的分子机制。该基金与经验丰富的专家指导小组和强有力的机构支持相结合，将为这位年轻的外科科学家提供一个高度创新的支持平台，以完成他的科学培训，并向再生医学领域的独立研究者过渡。

DESCRIPTION (provided by applicant): This new investigator proposal describes a 5-year training program for the development of a surgeon-scientist career in Pediatric and Fetal Surgery. After completing an MD degree, this investigator trained for 9 years in adult and pediatric general surgery that led to board certification in both of these fields. This time period included a near 3-year research fellowship under the mentorship of Timothy Crombleholme at the Children's Hospital of Philadelphia and Cincinnati Children's Hospital Medical Center (CCHMC). The main focus of this new investigator's work was the fetal regenerative wound healing response. He is currently an assistant professor of Pediatric and Fetal Surgery at Cincinnati Children's Hospital Medical Center. His career goals are to use this K08 award to support his commitment to develop as a highly skilled scientist and in the long term to transition to a successful, independent, NIH-funded surgeon-scientist. CCHMC has a long history of promoting and supporting young scientist careers. The institution has guaranteed the applicant 75% protected time to commit to his research effort. In the Department of Surgery, he is one of 20 general surgeons and there is strong departmental priority for research and ample resources to achieve this goal. In addition to the time commitment, the institution has provided a generous start-up fund package for the applicant, which includes lab space, research funds, and ancillary support for 5 years. In addition, since starting his faculty appointment in September 2009, the candidate has been awarded a highly competitive Procter Scholar Award that provides significant additional salary support and a KL2 that provides research funds and a rigorous oversight committee to monitor his progress for the current academic year. The cornerstone of the career development plan is an exemplary scientific advisory committee. The four scientists are from diverse backgrounds but prior collaborations exist within the group. Each member is considered an international authority in their field and more importantly have a long track record of supporting young scientists and providing effective mentorship. In addition, the candidate, in close consultation with the committee has outlined an educational plan that includes additional coursework, weekly lab meetings, national conferences, and an organized research plan to complete his training. This proposal investigates the underlying mechanism of the fetal regenerative phenotype. The applicant previously examined the role of IL-10 in the fetal wound healing response and the recapitulation of the fetal state in postnatal tissues via an attenuation of the inflammatory response. His new focus is to examine the IL- 10 mediated regulation of the extracellular matrix (ECM) in the fetal regenerative phenotype. The applicant developed a novel hypothesis that proposes IL-10 can result in the formation of a regenerative pericellular matrix by dermal fibroblasts via a STAT3-dependent mechanism. This concept of an immuno-modulator regulating the ECM is highly innovative. In the testing of this hypothesis, three aims are outlined. Aim 1 is to define the importance of IL-10 to the fetal fibroblast phenotype at the cellular level and then determine if IL-10 can recapitulate the fetal state in adult fibroblasts. Aim 2 elucidates the STAT3-mediated intracellular signal transduction of IL-10 in fibroblasts. Aim 3 is an in vivo validation of the hypothesis that effects of IL-10 in the regenerative phenotype are STAT3 and HAS1 mediated. Completion of these three aims ensures that there will be a clearer understanding of the underlying mechanisms of "fetal scarless wound healing" and that therapeutic targets may be identified for any disease characterized by excessive fibroplasia. Finally, the several new techniques and concepts learned during the 5-year grant period will facilitate the applicant's scientific training, thus providing him with new tools and hypotheses on which to build his future scientific career. In summary, this research and training proposal aims to understand the molecular mechanisms in the fetal regenerative response relative to wound healing. The grant in conjunction with an expert, experienced mentorship panel and strong institutional support would provide a highly innovative, supportive platform for this young surgeon-scientist to finish his scientific training and make the transition to independent investigator in the field of regenerative medicine.