NF Center: From animal models to therapeutics

1型神经纤维瘤病是一种遗传性疾病，对患者具有广泛的后果，从潜在的智力和认知缺陷到出现在周围神经系统的特发性肿瘤，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，目的是总结患者的各种病理特征。这一建议继续并扩展了我们在生成NFL相关神经纤维瘤的忠实基因组复制方面的经验。在该奖项资助的之前的工作中，我们的科学团队联手测试了雪旺细胞系外的NFL单倍体功能不全对丛状神经纤维瘤的发展做出了关键贡献的假设。这一假说来自对我们的小鼠模型的研究，结果揭示了肥大细胞在促进肿瘤表型方面的重要性，并最终导致了阻止患者肥大细胞活性的临床试验。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，识别真皮神经纤维瘤的来源和病因，并使用我们的MPNST模型来寻找治疗机会。在具体目标1中，我们将使用他莫昔芬可诱导的ERE驱动系和替代方法来更好地确定丛状神经纤维瘤的起源细胞来源，并确定肿瘤发展的时间窗口。在具体目标2中，我们将详述我们最近开发的皮肤神经纤维瘤小鼠模型，以及皮肤来源前体(SKP)是这些肿瘤的起源细胞这一发现。我们将使用多种技术，包括使用鸡/鹌鹑胚胎移植神经管来检查神经脊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三苯氧胺可诱导的转基因Cre驱动系，以探索神经脊源性组织的肿瘤潜能。最后，在特定的目标3，我们将筛选原代MPNST来源的肿瘤细胞，以承担小的化学和RNAi高通量筛选。这些筛选旨在识别小分子化合物和基因，这些小分子化合物和基因是 肿瘤细胞的增殖和生长，这可能成为治疗的靶点。

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.