Developing Human Induced Pluripotent Stem Cell Precision Oncology Models

摘要 该提案旨在支持一位研究专家，该专家正在利用 人类诱导多能干细胞（hiPSC）研究神经系统癌症生物学。这位专家 广泛的研究经验与RAS病癌症易感综合征，开始与她的博士学位 研究集中于产生面部皮肤和Costello综合征临床前斑马鱼模型， 在过去的六年里，作为一名博士后研究员，现在是一名研究员， 神经纤维瘤病1型（NF 1）因此，研究专家负责 华盛顿大学NF中心iPSC知识库的开发，第一个也是最大的NF 1集合 患者来源的和CRISPR/Cas9工程化的hiPSC。研究专家在生成和 NF 1-hiPSCs的部署促进了多个项目的开发、资助和积极参与 在项目主任的实验室内，以及涉及合作者的多机构项目 建模低度PNS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，研究专家开创了 的NF 1患者hiPSC系，以研究患者来源的NF 1基因突变对脑组织的差异影响。 功能障碍，特别是对神经系统RAS，cAMP和多巴胺信号传导，以及模型 携带Nf 1患者Nf 1基因的基因工程小鼠模型中的神经系统癌症发病机制 突变。总的来说，申请人利用她相当多的跨物种研究经验， 发展使用hiPSC模拟人类RAS相关癌症的专业知识。因此，她的hiPSC研究 揭示了与NF 1突变型神经系统肿瘤发病机制相关的重要新见解， Gutmann博士在NF 1精确肿瘤学方面的实验室研究。最后，她承诺 在华盛顿，继续在这一领域发挥领导作用，并协助指导基于iPSC的项目 大学和全球多个学术机构，极有可能提供临床可操作的 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.