Defining the Mechanistic Basis for Neurofibromatosis-1 Nervous System Disease Heterogeneity

项目摘要 随着我们进入个性化（精确）医疗时代，定义 影响疾病风险和结果的因素。由于这些决定因素在人类中不易控制， 流行病学研究、基因工程小鼠（GEM）品系和人诱导多能干细胞 多能干细胞（iPSC）系提供了机制上易于处理的平台，以定义疾病异质性的潜在因素。 并将其转化为风险评估工具和治疗方法。这一挑战很好地说明了 1型神经纤维瘤病（NF 1），一种罕见的神经遗传性疾病，由NF 1基因的种系突变引起。 NF 1患者容易出现各种神经系统问题，包括 认知和行为问题（60-70%的儿童）和低度脑肿瘤（约20%的儿童）。而 在婴儿中建立NF 1的诊断是简单的，目前还不可能预测哪一种 孩子未来会出现医疗问题，确定是否会出现需要的临床进展 治疗，或制定专门针对临床表现亚型的有效疗法， 单独的.临床医生和研究人员面临的紧迫挑战是解剖基因，细胞， 分子和系统水平的病因学为这些常见的神经系统问题的最终目标 为患有NF 1的儿童开发预后和精确的神经学方法。在这 根据这项提议，我们计划利用人类NF 1患者iPSC，即用患者生殖系NF 1基因改造的小鼠， 突变，生物信息学和系统生物学方法，以及新的建模方法， 定义NF 1异质性的基础因素。本项目的总体使命是 建立NF 1临床变异的病因学基础，并为未来的临床应用制定蓝图 因此，有必要将NF 1患者的护理从被动转为更主动的方法。

Project Summary As we enter into an era of personalized (precision) medicine, it becomes increasingly important to define the factors that confer disease risk and outcome. Since these determinants cannot be easily controlled in human epidemiological studies, genetically-engineered mouse (GEM) strains and human induced pluripotent stem cell (iPSC) lines provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. This challenge is nicely illustrated by Neurofibromatosis type 1 (NF1), a rare neurogenetic condition caused by a germline mutation in the NF1 gene. Individuals with NF1 are prone to the development of a wide variety of neurological problems, including cognitive and behavioral problems (60-70% of children) and low-grade brain tumors (~20% of children). While establishing the diagnosis of NF1 in an infant is straightforward, it is currently not possible to predict which child will develop future medical problems, determine whether there will be clinical progression requiring treatment, or institute effective therapies that specifically target the subtype of clinical manifestation in that individual. The pressing challenge for clinicians and researchers alike is to dissect the genetic, cellular, molecular, and systems-level etiologies for these common neurologic problems with the ultimate goal of developing prognostic and precision neurology approaches for children affected with NF1. In this proposal, we plan to leverage human NF1-patient iPSCs, mice engineered with patient germline NF1 gene mutations, bioinformatics and systems biology approaches, and novel modeling approaches to mechanistically define the factors that underlie the heterogeneity that characterizes NF1. The overall mission of this project is to establish the etiologic bases for NF1 clinical variability and to create a blueprint for future clinical application necessary to transform the care of individuals with NF1 from a reactive to a more proactive approach.