Novel Mechanisms of Regenerative Fetal Wound Repair by IL-10

IL-10 再生胎儿伤口修复的新机制

• 批准号: 8665993
• 负责人: Sundeep G Keswani
• 金额: $ 10.06万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665993
• 关键词: Adult; Advisory Committees; Animals; Appointment; Attenuated; Award; Binding Sites; Biological Assay; Board Certification; Cell Line; Characteristics; Childhood; Cicatrix; Collaborations; Commit; Complex; Consultations; Data; Deposition; Dermal; Development Plans; Disease; Ensure; Environment; Extracellular Matrix; Faculty; Fellowship; Fibroblasts; Funding; Future; Gene Expression; Gestational Age; Goals; Grant; Healed; Hyaluronan; In Vitro; Inflammatory; Inflammatory Response; Institution; Interleukin-10; International; Knockout Mice; Knowledge; Learning; Mediating; Medical center; Mentorship; Modeling; Molecular; Molecular Weight; Monitor; Morbidity - disease rate; Mus; Natural regeneration; Operative Surgical Procedures; Pathway interactions; Patients; Pediatric Hospitals; Pediatric Surgical Procedures; Phenotype; Philadelphia; Phosphorylation; Pregnancy; Production; Program Development; Property; Public Health; Recording of previous events; Regenerative Medicine; Regulation; Relative (related person); Research; Research Personnel; Research Priority; Research Training; Resources; Role; STAT3 gene; Scientist; Signal Transduction; Skin; Surgeon; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Training; Training Programs; United States National Institutes of Health; Validation; Wages; Work; Wound Healing; attenuation; authority; career; career development; chromatin immunoprecipitation; experience; fetal; fetus surgery; healing; in vivo; innovation; insight; investigator training; meetings; member; migration; novel; postnatal; professor; promoter; receptor; regenerative; response; small hairpin RNA; symposium; therapeutic target; tool; wound

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.

描述(由申请人提供)：这份新的研究提案描述了一项为期5年的培训计划，旨在发展儿科和胎儿外科的外科医生-科学家职业生涯。在完成医学学位后，这位研究员在成人和儿科普通外科方面接受了9年的培训，这导致了这两个领域的董事会认证。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)蒂莫西·克伦布尔霍尔姆(Timothy Crombleholme)指导下的近3年研究奖学金。这位新研究人员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的儿科和胎儿外科助理教授。他的职业目标是利用K08奖来支持他作为一名高技能科学家的发展承诺，并从长远来看，过渡到一名成功的、独立的、由NIH资助的外科医生兼科学家。CCHMC在促进和支持青年科学家事业方面有着悠久的历史。该机构已保证申请者75%的受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，有强烈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，该机构还为申请者提供了慷慨的创业资金包，其中包括实验室空间、研究资金和为期5年的辅助支持。此外，自2009年9月开始担任教师以来，候选人获得了竞争激烈的普罗科特学者奖，提供了大量的额外工资支持，并获得了KL2，提供研究资金和一个严格的监督委员会，以监督他在本学年的进展。职业发展计划的基石是一个模范的科学咨询委员会。这四位科学家来自不同的背景，但团队内部存在先前的合作。每个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磋商后，概述了一项教育计划，其中包括额外的课程作业、每周一次的实验室会议、全国会议和完成培训的有组织的研究计划。这项建议调查了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，以及通过减弱炎症反应在出生后组织中重现胎儿状态的作用。他的新重点是研究IL-10在胎儿再生表型中对细胞外基质(ECM)的调节。申请人提出了一个新的假设，即IL-10可以通过STAT3依赖的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细胞外基质的概念具有很高的创新性。在检验这一假说的过程中，概述了三个目标。目的1在细胞水平上明确IL-10对胎儿成纤维细胞表型的重要性，进而确定IL-10能否在成人成纤维细胞中再现胎儿状态。目的2阐明STAT3介导的IL-10在成纤维细胞内的信号转导。目的3是对IL-10在再生表型中的作用是STAT3和HAS1介导的假说的体内验证。完成这三个目标将确保更清楚地了解“胎儿无疤痕伤口愈合”的潜在机制，并可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年资助期内学到的几种新技术和新概念将促进申请人的科学培训，从而为他提供新的工具和假设，以建立他未来的科学事业。总之，这项研究和培训计划旨在了解胎儿再生反应中与伤口愈合相关的分子机制。这笔赠款加上一个经验丰富的专家导师小组和强有力的机构支持，将为这位年轻的外科科学家提供一个高度创新和支持的平台，以完成他的科学培训，并过渡到再生医学领域的独立研究人员。

项目成果

Fetal wound healing: implications for minimal scar formation.

• DOI: 10.1097/mop.0b013e3283535790
• 发表时间: 2012-06
• 期刊: Current opinion in pediatrics
• 影响因子: 3.6
• 作者: Leung A;Crombleholme TM;Keswani SG
• 通讯作者: Keswani SG

Interleukin-10 regulates fetal extracellular matrix hyaluronan production.

• DOI: 10.1016/j.jpedsurg.2013.03.014
• 发表时间: 2013-06
• 期刊: JOURNAL OF PEDIATRIC SURGERY
• 影响因子: 2.4
• 作者: King, Alice;Balaji, Swathi;Le, Louis D.;Marsh, Emily;Crombleholme, Timothy M.;Keswani, Sundeep G.
• 通讯作者: Keswani, Sundeep G.