NF Center: From Animal Models to Therapeutics

描述（申请人提供）： NF 1基因的失活是神经系统最常见的遗传性疾病之一，神经纤维瘤病1型的根本原因。神经纤维蛋白是NF-1的基因产物，编码一个3000个氨基酸的蛋白质，该蛋白质含有ras途径的负调节因子rasGT 3激活结构域（rasGAP）。迄今为止，普遍的证据表明，所有与神经纤维瘤病相关的病理是ras信号失调的结果。患病个体中最常见的肿瘤病理是神经纤维瘤（100%发病率）、恶性外周神经鞘瘤（15%发病率）、视神经胶质瘤（毛细胞星形细胞瘤; 20%发病率）和星形细胞瘤（<1%发病率）。我们试图在小鼠中建立这些肿瘤的模型，作为了解起源、进展的分子细节和开发潜在治疗方法的一种手段。小鼠敲除模型的初始开发产生了关于发育中NF 1的大量信息，无效表型导致胚胎致死，从而限制了我们将NF 1作为肿瘤抑制因子进行检查的能力（Brannan et al.，1994年）。将NF 1和p53肿瘤抑制因子的生殖系突变结合起来的遗传技巧导致小鼠产生100%突变率的MPNST。这一结果首次表明小鼠NF 1基因的突变可以有效地模拟人肿瘤状况（Vogel et al.，1998年）。为了实现对NF 1建模的更好控制，我们已经通过使用cre/lox技术开发了组织特异性突变（Zhu等人，2000年）。使用条件性基因敲除，我们已经成功地模拟了丛状神经纤维瘤的形成，从而确定了肿瘤起源的局部细胞和肿瘤发展中远端伙伴的重要性。这个应用程序的重点是我们的信念，即遥远的合作伙伴是一个肥大细胞。此外，我们有新的模型，表现出肿瘤的中枢神经系统：即视神经胶质瘤和星形细胞瘤。在本申请中，我们提出发展更好地理解视神经胶质瘤的发生。此外，我们将与我们的同事克拉普博士和英格拉姆博士在肥大细胞对神经纤维瘤形成的分子研究接口。

Description (provided by applicant): Inactivation of the NF1 gene is the underlying cause for one of the most common genetic diseases of the nervous system, neurofibromatosis type 1. Neurofibromin, the gene product of NF1encodes for a 3000 amino acid protein that contains a rasGTPase activating domain (rasGAP), a negative regulator of the ras pathway. To date, prevailing evidence indicates that all pathologies associated with neurofibromatosis are the consequence of deregulation of ras signaling. The most common tumor pathologies in afflicted individuals are neurofibromas (100% incidence), malignant peripheral nerve sheath tumors (15% incidence), optic gliomas (pilocytic astrocytomas; 20% incidence), and astrocytomas (<1% incidence). We have attempted to model these tumors in mice as a means of understanding the origin, molecular details of progression, and to develop potential therapies. Initial development of mouse knockout models yielded considerable information on NF1 in development, the null phenotype resulted in embryonic lethality thus limiting our ability to examine NF1 as a tumor suppressor (Brannan et al., 1994). The genetic trick of combining germline mutations at the NF1 and p53 tumor suppressors resulted in mice that developed MPNSTs with 100% penetrance. This result provided the first indication that mutations in the mouse NF1 genes could mimic the human tumor condition effectively (Vogel et al., 1998). To achieve better control of the NF1 modeling, we have developed tissue specific mutations by use of cre/lox technology (Zhu et al., 2000). Using conditional knockouts, we have successfully modeled formation of plexiform neurofibromas, thus identifying the local cell of tumor origin and the importance of a distant partner in tumor development. Much of this application focuses on our conviction that the distant partner is a mast cell. In addition we have new models that exhibit tumors of the CNS: namely optic tract gliomas and astrocytomas. In the present application we propose to develop a greater understanding of the genesis of optic gliomas. In addition, we will interface with our colleagues Dr. Clapp and Dr. Ingram in molecular studies of mast cell contribution to neurofibroma formation.