NF Center: From animal models to therapeutics

1型神经纤维瘤病是一种遗传性疾病，对患者有广泛的影响，从潜在的智力和认知缺陷到周围神经系统特发性肿瘤的出现，统称为神经纤维瘤。在过去的12年里，我们开发了NFl的小鼠模型，目的是概括患者的各种病理特征。本建议延续并扩展了我们在产生忠实的nfl相关神经纤维瘤种族分类方面的经验。在之前由该奖项资助的工作中，我们的科学团队联合起来验证了雪旺细胞谱系外的NFl单倍体缺陷对丛状神经纤维瘤的发展起关键作用的假设。这一假设来自我们的小鼠模型研究，结果揭示了肥大细胞在促进肿瘤表型方面的重要性，并最终导致临床试验阻断患者的肥大细胞活性。在目前的应用中，我们建议扩展我们的小鼠建模能力，以进一步了解丛状神经纤维瘤的病因，确定真皮神经纤维瘤的来源和病因，并使用我们的MPNST模型寻找治疗机会。在Specific Aim 1中，我们将采用他莫昔芬诱导的驱动细胞系和其他方法来更好地定义丛状神经纤维瘤的细胞来源，并定义肿瘤发展的能力时间窗口。在特异性目标2中，我们将扩展我们最近开发的真皮神经纤维瘤小鼠模型，并发现皮肤源性前体（SKPs）是这些肿瘤的起源细胞。我们将使用多种技术，包括使用鸡/鹌鹑胚胎神经管移植来检查神经嵴是否是这些肿瘤活性细胞的原始来源。我们还将开发新的有价值的他莫昔芬诱导转基因Cre驱动系，以探测神经嵴源性组织的肿瘤潜力。最后，在Specific Aim 3中，我们将筛选原发mpnst衍生的肿瘤细胞，进行小化学和RNAi高通量筛选。这些筛选旨在识别小分子化合物和基因所需的

Neurofibromatosis type 1 is a genetic disease with wide ranging consequences on the afflicted individuals ranging from potential intellectual and cognitive deficits to appearance of idiopathic tumors in the peripheral nervous system collectively called neurofibromas. Over the past 12 years we have developed mouse models of NFl with the objective of recapitulating a variety of the pathologic features seen in patients. This proposal continues and expands upon our experience in generating faithful genocopies of NFl-associated neurofibromas. In preceding work funded by this award, our scientific teams joined forces to test the hypothesis that NFl haploinsufficiency outside the Schwann cell lineage provided critical contribution to plexiform neurofibroma development. This hypothesis emerged from studies with our mouse models and the outcome has revealed the importance of mast cells in contributing to the tumor phenotype and ultimately leading to clinical trials to block mast cell activity in patients. In the present application we propose to extend our mouse modeling capabilities to further understand the etiology of plexiform neurofibromas, to identify the source and etiology of dermal neurofibromas, and to use our MPNST models to seek out therapeutic opportunities. In Specific Aim 1, we will employ tamoxifen-inducible ere driver lines and alternative approaches to better define the source of the cell of origin for plexiform neurofibromas and to define the temporal window of competence for tumor development. In Specific Aim 2, we will expand on our recent development of a murine model for dermal neurofibromas and on the discovery that skin-derived precursors (SKPs) are the cell of origin for these tumors. We will use multiple techniques including the use of chick/quail embryo transplantation of neural tubes to examine whether the neural crest is the original source of these tumor-competent cells. We will also develop new valuable tamoxifeninducible transgenic Cre driver lines to probe the neural crest-derived tissues for tumor potential. Finally, in Specific Aim 3, we will screen primary MPNST-derived tumor cells to undertake small chemical and RNAi highthroughput screens. These screens aim to identify small molecule compounds and genes that are required for tumor cell proliferation and growth and that can become targets for therapeutics.