DEFINING RISK FACTORS FOR NF1-OPTIC GLIOMA

定义 NF1 视神经胶质瘤的危险因素

• 批准号: 9333268
• 负责人: David H Gutmann
• 金额: $ 34.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333268
• 关键词: Affect; Apoptosis; Assessment tool; Attenuated; Biological Markers; Blindness; Brain Neoplasms; Cell Death; Cell Survival; Child; Childhood; Clinical; Cyclic AMP; Development; Disease; Disease Outcome; Female; Fibroblasts; Frameshift Mutation; Functional disorder; GPER gene; Gene Mutation; Generations; Genetically Engineered Mouse; Glial Fibrillary Acidic Protein; Glioma; Gonadal Steroid Hormones; Growth; Hormonal; Hormone Receptor; Human; Impairment; Individual; Inherited; Intervention; Laboratories; Malignant Childhood Neoplasm; Medical; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; NF1 gene; Neoplasms; Neurofibromatosis 1; Neurofibromatosis Type 1 Protein; Neurological outcome; Neuronal Dysfunction; Operative Surgical Procedures; Optic Nerve; Optic Nerve Glioma; Optical Coherence Tomography; Optics; Outcome; Pathway interactions; Patients; Pharmacology; Predisposition; Radiation; Retinal; Retinal Ganglion Cells; Risk; Risk Assessment; Risk Factors; Series; Serum; Syndrome; System; Tamoxifen; Therapeutic; Thick; Thinness; Translating; Vision; Visual; Visual Acuity; Visual impairment; base; chemotherapy; clinical care; clinical predictors; disease heterogeneity; disorder risk; epidemiology study; experience; experimental study; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; male; mutant; neurofilament; novel; novel strategies; patient population; personalized medicine; potential biomarker; pre-clinical; preclinical study; prevent; prognostic; receptor; retinal nerve fiber layer; sex; therapy outcome; tumor; virtual

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.

项目概要 随着我们进入个性化医疗时代，定义影响个体化医疗的因素变得越来越重要。 赋予疾病风险和结果。由于这些决定因素在人类中不容易控制 流行病学研究，基因工程小鼠（GEM）品系提供机械上易于处理的 定义疾病异质性背后因素并将其转化为风险评估工具的平台 和治疗。儿童低度脑肿瘤（神经胶质瘤）是一种具有挑战性的疾病， 预测临床进展、优化治疗和改善神经系统结果。在最 儿童低级别胶质瘤、1 型神经纤维瘤病 (NF1) 的常见遗传原因，15-20% 的儿童 发展为视神经胶质瘤 (OPG)，导致 30-60% 受影响个体视力下降。然而，它 目前无法预测哪个患有 NF1 的儿童会出现 OPG 或谁会出现视力障碍 因肿瘤而衰退或失明。我们有能力识别 OPG 发展风险最大的儿童 视力丧失将提供重要的具有临床意义的预后信息，以指导临床护理 准确的视觉评估可能具有挑战性的前语言患者群体。最近的观察 表明特定种系 NF1 基因突变可能是 OPG 发展的危险因素之一，而 患者性别影响 OPG 相关的视力下降。在这方面，患有 NF1 相关 OPG 的儿童 更有可能携带特定类型的种系 NF1 基因突变（5' 端移码突变）。此外， 我们最近发现，患有 NF1 的女童和小鼠更容易因以下原因而出现视力丧失： 他们的 OPG。基于这些令人兴奋的发现，我们假设特定的种系 NF1 基因 突变和性激素是 OPG 发生和进展的独立危险因素， 分别。在本提案中，我们的目标是严格确定特定 NF1 基因突变如何决定 OPG 形成并定义观察到的两性 OPG 相关视力丧失的分子基础 使用一系列新颖的 Nf1 GEM 菌株和方法。由此产生的结果将被用来 临床前评估识别有 OPG 发育和视力风险的 NF1 儿童的新方法 损失以及减轻或预防 NF1-OPG 相关的潜在替代治疗方法 视力下降。