DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA

项目摘要 随着我们进入个性化医疗时代，定义以下因素变得越来越重要 提供疾病风险和结果。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)品系提供了机械上易驯化的 定义疾病异质性的潜在因素并将其转化为风险评估工具的平台 和治疗。儿童低级别脑瘤(胶质瘤)是一种具有挑战性的疾病 在预测临床进展、优化治疗和改善神经学结果方面。在大多数情况下 儿童低级别神经胶质瘤的常见遗传原因，1型神经纤维瘤病(NF1)，15%-20%的儿童 发生视路胶质瘤(OPG)，导致30%-60%的受影响个体视力下降。然而，它 目前还不能预测哪个NF1儿童会出现OPG，或者谁会有视觉障碍 因肿瘤而衰退或失明。我们识别OPG发育风险最大的儿童的能力 视力丧失将提供重要的临床有意义的预后信息来指导临床治疗 言语前患者群体，其中准确的视觉评估可能是具有挑战性的。最近的观察结果 提示生殖系NF1基因突变可能是OPG发生的危险因素之一。 患者性别影响与OPG相关的视力下降。在这方面，患有NF1相关OPG的儿童是 更有可能存在特定类型的生殖系NF1基因突变(5‘端移码突变)。此外, 我们最近的研究表明，患有NF1的女性儿童和小鼠更容易出现视力丧失 他们的OPG。基于这些具有挑衅性的发现，我们假设特定的生殖系NF1基因 突变和性激素是OPG发生和发展的独立危险因素， 分别进行了分析。在这项建议中，我们旨在关键地确定特定的nf1基因突变是如何决定OPG的。 观察到的性二型OPG相关性视力丧失的形成和分子基础 使用一系列新的NF1 GEM菌株和方法。由此产生的结果将被用来 临床前评估识别NF1儿童OPG发育和视力风险的新方法 减少或预防NF1-OPG相关的损失以及潜在的替代治疗方法 视觉衰退。

Project Summary As we enter into an era of personalized 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 provide mechanistically-tractable platforms to define the factors underlying disease heterogeneity and translate them to risk assessment tools and treatments. Pediatric low-grade brain tumors (gliomas) represent one such challenging disease with respect to predicting clinical progression, optimizing treatment, and improving neurologic outcome. In the most common inherited cause for pediatric low-grade glioma, neurofibromatosis type 1 (NF1), 15-20% of children develop optic pathway gliomas (OPGs), leading to visual decline in 30-60% of affected individuals. However, it is not currently possible to predict which child with NF1 will develop an OPG or who will experience visual decline or blindness from their tumor. Our ability to identify those children at greatest risk for OPG development and vision loss would provide important clinically-meaningful prognostic information to guide clinical care for a pre-verbal patient population in which accurate visual assessments can be challenging. Recent observations suggest that the specific germline NF1 gene mutation may be one risk factor for OPG development, whereas patient sex influences OPG-associated visual decline. In this regard, children with NF1-associated OPGs are more likely to harbor specific types of germline NF1 gene mutations (5' end frameshift mutations). In addition, we have recently shown that female children and mice with NF1 more frequently experience visual loss from their OPGs. Based on these provocative findings, we hypothesize that the particular germline NF1 gene mutation and gonadal sex hormones are independent risk factors for OPG development and progression, respectively. In this proposal, we aim to critically determine how the specific NF1 gene mutation dictates OPG formation and define the molecular basis for the observed sexually-dimorphic OPG-associated vision loss using a novel series of Nf1 GEM strains and approaches. The resulting outcomes will be leveraged to preclinically evaluate new approaches to identifying children with NF1 at risk for OPG development and vision loss as well as potential alternative therapeutic approaches for attenuating or preventing NF1-OPG-related visual decline.