DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA

项目摘要 随着我们进入个性化医疗的时代，定义 带来疾病风险和结果。由于这些决定因素在人类中不易控制， 在流行病学研究中，基因工程小鼠（GEM）品系提供了机械上易处理的 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。儿童低级别脑肿瘤（神经胶质瘤）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局方面。最 儿童低级别胶质瘤的常见遗传原因，1型神经纤维瘤病（NF 1），15-20%的儿童 发展成视神经胶质瘤（OPG），导致30-60%的受影响个体视力下降。但 目前无法预测哪些NF 1儿童将发展OPG或谁将经历视觉障碍。 因肿瘤而衰退或失明。我们有能力识别出OPG发育风险最大的儿童 和视力丧失将提供重要的临床意义的预后信息，以指导临床护理， 言语前患者人群，其中准确的视觉评估可能具有挑战性。最近的观察 提示特定的生殖系NF 1基因突变可能是OPG发生的一个危险因素，而 患者性别影响OPG相关视力下降。在这方面，患有NF 1相关OPG的儿童 更可能具有特定类型的种系NF 1基因突变（5'端移码突变）。此外，本发明还提供了一种方法， 我们最近的研究表明，患有NF 1的女童和小鼠更经常地经历视力丧失， 他们的OPG。基于这些令人激动的发现，我们假设特定的生殖系NF 1基因 突变和性腺性激素是OPG发生和进展的独立危险因素， 分别在这个建议中，我们的目标是严格确定特定的NF 1基因突变如何决定OPG 形成和定义观察到的性二态OPG相关视力丧失的分子基础 使用一系列新的Nf 1 GEM菌株和方法。将利用由此产生的成果， 临床前评估新的方法，以确定儿童与NF 1在OPG的发展和视力的风险 以及用于减弱或预防NF 1-OPG相关的潜在替代治疗方法 视力下降

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.