Therapeutic Mechanisms of Placental Stem Cell-Based Therapy in Necrotizing Enterocolitis

项目总结 该应用程序的总体目标是支持NIDDK指导的研究科学家发展奖 (K01)申请人Victoria Weis博士，博士，位于儿童肠道上皮细胞生物学的交叉点 疾病和新的翻译疗法来研究坏死性小肠结肠炎(NEC)，一种毁灭性的肠道 影响最脆弱早产儿的疾病。目前还没有有效的治疗方法， 死亡率保持在20%-40%。随着NEC风险最高的早产儿人数继续上升 由于NICU护理的全面改善，迫切需要开发创新的临床 抗击这种疾病的可翻译疗法。尽管几十年的研究旨在揭示风险因素 对于NEC的发病机制，该领域还没有发展到临床可用治疗的地步。我们 假设阻碍临床可翻译候选治疗发展的关键障碍是缺乏 对涉及NEC修复和上皮修复的补救动态机制的理解。我们的 该小组最近在使用从胎盘组织中分离的围产期干细胞方面取得了令人振奋的结果 通过调节炎症反应和重建 肠道干细胞巢和上皮屏障。我们假设胎盘干的双重支持作用 细胞对免疫的调节和上皮细胞的再生将使我们能够揭示其动态机制 负责启动NEC的肠道修复，以指导进一步的高级治疗开发工作。 本申请的具体目标反映了对所涉及的机制和时间进程的严格研究 胎盘干细胞衰减率检测：(1)NEC体内修复细胞和分子动力学 肠损伤和(2)靶向对内皮细胞损伤的体外直接治疗作用 转化为人类NEC疾病。此外，还制定了全面的职业发展计划 这支持了Weis博士继续的科学成长和转变为一名独立的研究人员 儿科肠道疾病模型，以识别、表征和翻译新的治疗方法。一位专家 跨新的翻译干细胞疗法、体外器官/疾病领域的多学科委员会 建模、高级成像和分析、胃肠病学和新生儿学已经组装完毕，并将 为韦斯博士的职业轨迹提供指导。这份职业发展计划补充了Weis博士现有的 胃肠道细胞生物学和动物疾病模型开发/表征方面的技能和专业知识 通过先进的教学课程，新技能的指导，以及体外模型系统的实验室培训， 新疗法和转化性研究。与其他基本技能的指导和建议相结合 (例如，拨款撰写、预算编制、人事管理)，这个职业发展奖将确保成功 作为一名在儿科肠道翻译方面接受过独特培训的研究人员过渡到独立 作为一名独立调查员，Weis博士在职业生涯早期就对疾病产生了重大影响。

PROJECT SUMMARY The overall goal of this application is to support a NIDDK Mentored Research Scientist Development Award (K01) for the applicant, Dr. Victoria Weis, PhD, at the intersection of epithelial cell biology, pediatric intestinal disease, and novel translational therapeutics to study necrotizing enterocolitis (NEC), a devastating intestinal disease affecting the most fragile premature infants. There are no effective therapies currently available and mortality rates persist at 20-40%. As the population of premature infants at highest risk for NEC continues to rise due to overall improvements in NICU care, an urgent need has emerged to develop innovative clinically translatable therapies to combat this disease. Despite decades of research targeted at uncovering the risk factors and mechanisms for onset of NEC, the field has not progressed to the point of clinically available therapies. We posit that a critical barrier preventing the development of clinically translatable therapeutic candidates is the lack of understanding in the remedial dynamic mechanisms involved in NEC repair and epithelial restitution. Our group has recently shown promising results with the use of perinatal stem cells isolated from placental tissue in facilitating the reparative process through regulation of the inflammatory response and re-establishment of the intestinal stem cell niche and epithelial barrier. We hypothesize that the dual supportive role of placental stem cells on immune modulation and epithelial regeneration will enable us to uncover the dynamic mechanisms responsible for initiating intestinal repair in NEC, to guide further efforts in advanced therapeutic development. The specific aims of this application reflect a rigorous study of the mechanisms and time-course involved in placental stem cell attenuation of NEC to examine: (1) reparative cellular and molecular dynamics in in vivo NEC intestinal damage and (2) direct therapeutic effects specifically on NEC damaged epithelium in vitro with targeted translation into human NEC disease. In addition, a comprehensive career development plan has been developed that supports Dr. Weis’s continued scientific growth and transition into an independent investigator studying pediatric intestinal disease models to identify, characterize, and translate novel therapeutics. An expert multidisciplinary committee across the fields of novel translational stem cell therapy, in vitro organ/disease modeling, advanced imaging and analysis, gastroenterology, and neonatology have been assembled and will provide guidance for Dr. Weis’s career trajectory. This career development plan supplements Dr. Weis’s existing skill-set and expertise in gastrointestinal cell biology and development/characterization of animal disease models with advanced didactic coursework, mentoring in new skills, and laboratory training in in vitro model systems, novel therapeutics, and translational research. Combined with mentoring and advising in other essential skills (e.g. grant writing, budgeting, personnel management), this career development award will ensure successful transition into independence as a uniquely trained investigator in translational aspects of pediatric intestinal diseases, enabling Dr. Weis to make important impacts early in her career as an independent investigator.