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

胎盘干细胞治疗坏死性小肠结肠炎的治疗机制

• 批准号: 10301846
• 负责人: Victoria Weis
• 金额: $ 13.55万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301846
• 关键词: Address; Affect; Animal Disease Models; Attenuated; Biological Models; Budgets; Caring; Cells; Cellular biology; Childhood; Clinical; Clinical Treatment; Data; Development; Development Plans; Disease; Disease model; Doctor of Philosophy; Engraftment; Ensure; Epithelial; Epithelial Cells; Foundations; Gastroenterology; Goals; Grant; Growth; Human; Image; Immune; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intestinal Diseases; Intestines; Investigation; K-Series Research Career Programs; LGR5 gene; Life; Lymphocyte; Lymphocyte Subtypings; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Necrotizing Enterocolitis; Neonatology; Operative Surgical Procedures; Organ; Paracrine Communication; Pathogenicity; Pathway interactions; Perinatal; Personnel Management; Placenta; Population; Premature Infant; Prevention; Process; Rattus; Recovery; Regulation; Regulatory T-Lymphocyte; Reproducibility; Research; Research Personnel; Resected; Resolution; Risk Factors; Role; Signal Transduction; Survival Rate; Targeted Research; Therapeutic; Therapeutic Effect; Therapeutic Human Experimentation; Time; Tissues; Translating; Translational Research; Translations; Writing; attenuation; base; career; career development; clinical development; clinically translatable; combat; effective therapy; epithelial repair; epithelium regeneration; gastrointestinal; healing; high risk; human disease; immunoregulation; improved; in vitro Model; in vivo; inflammatory milieu; innovation; intestinal epithelium; investigator training; laboratory experience; molecular dynamics; mortality; multidisciplinary; novel; novel therapeutics; patient population; placental stem cell; premature; prevent; pup; regeneration function; repaired; reparative process; restoration; skills; skills training; stem cell niche; stem cell survival; stem cell therapy; stem cells; stem-like cell; targeted treatment; therapeutic candidate; therapeutic development; therapeutically effective; therapy development

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.

项目摘要 该应用程序的总体目标是支持NIDDK指导研究科学家发展奖 (K01)对于申请人，维多利亚韦斯博士，博士，在上皮细胞生物学，儿科肠道 疾病，和新的转化疗法研究坏死性小肠结肠炎（NEC），一个破坏性的肠道 影响最脆弱的早产儿的疾病。目前没有有效的治疗方法， 死亡率持续在20- 40%。随着NEC风险最高的早产儿人数继续增加， 由于NICU护理的整体改善，迫切需要开发创新的临床 可翻译的疗法来对抗这种疾病。尽管数十年来的研究旨在揭示风险因素， 和NEC发病的机制，该领域还没有发展到临床上可用的治疗方法。我们 认为阻碍临床上可转化的治疗候选药物发展的一个关键障碍是缺乏 对NEC修复和上皮恢复所涉及的治疗动态机制的理解。我们 最近，一个研究小组利用从胎盘组织中分离的围产期干细胞， 促进修复过程，通过调节炎症反应和重建 肠干细胞龛和上皮屏障。我们假设胎盘干的双重支持作用 细胞对免疫调节和上皮再生的作用将使我们能够揭示其动态机制， 负责启动NEC的肠修复，以指导高级治疗开发的进一步努力。 本申请的具体目的反映了对参与的机制和时间过程的严格研究， 胎盘干细胞衰减NEC检查：（1）修复细胞和分子动力学在体内NEC 肠损伤和（2）靶向的体外特异性对NEC损伤上皮的直接治疗作用 转化为人类NEC疾病。此外，还制定了全面的职业发展计划 支持Weis博士的持续科学成长和转变为一名独立的研究者， 儿科肠道疾病模型，以确定，表征和翻译新的治疗方法。专家 跨新型转化干细胞治疗、体外器官/疾病领域的多学科委员会 建模，先进的成像和分析，胃肠病学，和消化病学已经组装，并将 为韦斯博士的职业生涯提供指导这个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， 新疗法和转化研究。结合其他基本技能的指导和建议 (e.g.拨款写作，预算编制，人事管理），这个职业发展奖将确保成功 过渡到独立作为一个独特的培训研究者在翻译方面的儿科肠道 疾病，使Weis博士能够在她作为独立研究者的职业生涯早期产生重要影响。