Developing Human Induced Pluripotent Stem Cell Precision Oncology Models

摘要 此提案旨在支持一名研究专家，该专家正在带头开展多项计划， 人诱导多能干细胞(HiPSCs)用于神经系统肿瘤生物学研究。这位专家有 从她的博士开始，就有了广泛的研究经验--关于类风湿性癌症易感综合征 研究重点是建立心脏-面部-皮肤和Costello综合征临床前斑马鱼模型， 在过去的六年里，作为博士后研究员和现在的职员科学家，开发翻译研究 治疗1型神经纤维瘤病的工具(NF1)。因此，研究专家负责 开发华盛顿大学NF中心IPSC知识库，这是NF1的第一个也是最大的集合 患者来源的和CRISPR/Cas9工程的HiPSCs。研究专家在生成和处理数据方面的专业知识 部署NF1-hiPSC促进了多个项目的开发、资金和积极参与 在计划主任的实验室内，以及涉及合作者的多机构计划内 模拟低级别三叉神经节肿瘤、恶性肿瘤进展、小胶质细胞对神经系统的贡献 肿瘤和癌症中的神经元功能障碍。此外，研究专家是开发的先驱 研究患者来源的NF1基因突变对大脑的不同影响 功能障碍，特别是对神经系统RAS、cAMP和多巴胺信号的影响，以及模型 NF1患者NF1基因工程小鼠神经系统肿瘤发病机制的研究 突变。总的来说，申请者利用她丰富的跨物种研究经验 发展使用HiPSCs来模拟人类RAS相关癌症的专业知识。因此，她的HiPSC研究已经 揭示了与NF1突变神经系统肿瘤的发病机制相关的重要新见解 帮助指导了古特曼博士在NF1精确肿瘤学方面的实验室研究。最后，她致力于 在这一领域继续发挥领导作用，并在华盛顿协助指导以IPSC为基础的项目 大学和世界各地的多个学术机构，极有可能提供临床上可操作的 与RAS相关患者的个性化风险评估和医疗管理相关的机会 肿瘤学疾病。

Abstract This proposal is designed to support a Research Specialist who is spearheading numerous initiatives using human induced pluripotent stem cells (hiPSCs) to study nervous system cancer biology. This specialist has extensive research experience with RASopathy cancer predisposition syndromes, beginning with her doctoral studies focused on generating Cardio-Facial-Cutaneous and Costello Syndrome preclinical zebrafish models, and over the past six years as a postdoctoral fellow and now Staff Scientist, developing translational research tools for Neurofibromatosis Type 1 (NF1). As such, the Research Specialist was responsible for the development of The Washington University NF Center iPSC Repository, the first and largest collection of NF1 patient-derived and CRISPR/Cas9-engineered hiPSCs. The Research Specialist’s expertise in generating and deploying NF1-hiPSCs has galvanized the development, funding and active participation in multiple projects within the Program Director’s laboratory, as well as multi-institutional programs involving collaborators modeling low-grade PNS tumors, malignant cancer progression, microglia contributions to nervous system tumor, and neuronal dysfunction in cancer. Moreover, the Research Specialist has pioneered the development of NF1 patient hiPSC lines to study the differential impact of patient-derived NF1 gene mutations on brain dysfunction, and specifically on nervous system RAS, cAMP and dopamine signaling, as well as to model nervous system cancer pathogenesis in genetically-engineered mouse models harboring NF1 patient Nf1 gene mutations. Collectively, the applicant has leveraged her considerable cross-species research experience to develop expertise in using hiPSCs to model human RAS-related cancer. As such, her hiPSC studies have revealed important new insights relevant to the pathogenesis of NF1-mutant nervous system tumors, which have helped to guide Dr. Gutmann’s laboratory studies in NF1 precision oncology. Finally, her commitment to the field, continued leadership in this area, and assistance in guiding iPSC-based projects, both at Washington University and at multiple academic institutions worldwide, are highly likely to provide clinically-actionable opportunities relevant to personalized risk assessment and medical management of people with RAS-related oncologic disease.