NF Center: From animal models to therapeutics

1型神经纤维瘤病是一种遗传性疾病，对患病个体具有广泛的后果，从潜在的智力和认知缺陷到外周神经系统中特发性肿瘤的出现，统称为神经纤维瘤。在过去的12年中，我们已经开发了NF 1的小鼠模型，目的是重现在患者中观察到的各种病理学特征。该提议继续并扩展了我们在产生NF相关神经纤维瘤的忠实基因组拷贝方面的经验。在该奖项资助的之前工作中，我们的科学团队联手测试了这样的假设：雪旺细胞谱系之外的NF 1单倍不足对丛状神经纤维瘤的发育做出了关键贡献。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成肿瘤表型方面的重要性，并最终导致临床试验以阻断患者中肥大细胞的活性。在本申请中，我们提出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，以确定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，我们将采用他莫昔芬诱导的ere驱动线和替代方法，以更好地确定丛状神经纤维瘤起源细胞的来源，并确定肿瘤发展的时间窗口。在具体目标2中，我们将扩大我们最近开发的皮肤神经纤维瘤小鼠模型，并发现皮肤来源的前体细胞（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/鹌鹑胚胎移植的神经管，以检查是否神经嵴是这些肿瘤细胞的原始来源。我们还将开发新的有价值的他莫昔芬诱导型转基因Cre驱动系，以探测神经嵴来源的组织的肿瘤潜力。最后，在特定目标3中，我们将筛选原发性MPNST衍生的肿瘤细胞，以进行小化学和RNAi高通量筛选。这些筛选旨在鉴定小分子化合物和基因， 肿瘤细胞增殖和生长，并且可以成为治疗的靶点。

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.