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)医学时代，定义 决定疾病风险和结果的因素。由于这些决定因素在人类体内不容易控制 流行病学研究，基因工程小鼠(GEM)品系和人类诱导的多能干细胞 (IPSC)系列提供了机械上易于处理的平台，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。这一挑战在以下方面得到了很好的说明 神经纤维瘤病1型(NF1)，一种罕见的神经遗传学疾病，由NF1基因的胚系突变引起。 患有NF1的人容易出现各种神经问题，包括 认知和行为问题(60%-70%的儿童)和低级别脑瘤(约20%的儿童)。而当 在婴儿中确定NF1的诊断很简单，目前还不可能预测哪种情况 孩子将来会出现医疗问题，决定是否会有临床进展需要 治疗，或制定专门针对临床表现亚型的有效疗法 个人的。临床医生和研究人员面临的紧迫挑战是剖析基因、细胞和 这些常见神经问题的分子和系统水平的病因最终目标是 为受NF1影响的儿童开发预后和精确的神经学方法。在这 提案中，我们计划利用人类NF1患者iPSCs，即用患者生殖系NF1基因改造的小鼠 突变、生物信息学和系统生物学方法，以及新的机械建模方法 定义构成NF1异质性特征的因素。该项目的总体任务是 建立NF1临床变异的病因学基础，勾画未来临床应用蓝图 有必要将对NF1患者的护理从被动方式转变为更主动的方式。

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.