NF Center: From Animal Models to Therapeutics

描述(由申请人提供)： NF1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。NF1的基因产物神经纤维蛋白编码3000个氨基酸的蛋白质，含有rasGTPase激活结构域(RasGTP)，ras途径的负调节因子。到目前为止，普遍的证据表明，所有与神经纤维瘤病相关的病理都是ras信号失控的结果。最常见的肿瘤病理是神经纤维瘤(100%发生率)、恶性周围神经鞘瘤(15%发生率)、视神经胶质瘤(毛细胞性星形细胞瘤，20%发生率)和星形细胞瘤(1%发生率)。我们试图在小鼠身上建立这些肿瘤的模型，以此来了解肿瘤的起源、进展的分子细节，并开发潜在的治疗方法。小鼠基因敲除模型的最初发展产生了大量关于NF1发育中的信息，零表型导致胚胎死亡，从而限制了我们将NF1作为肿瘤抑制因子研究的能力(Brannan等人，1994)。结合NF1和P53肿瘤抑制基因胚系突变的遗传技巧导致小鼠发育出100%外显率的MPNSTs。这一结果首次表明，小鼠NF1基因的突变可以有效地模拟人类肿瘤的情况(Vogel等人，1998)。为了更好地控制NF1建模，我们利用cre/lox技术开发了组织特异性突变(朱等人，2000年)。使用条件性基因敲除，我们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远处伴侣在肿瘤发展中的重要性。这个应用程序的很大一部分都集中在我们的信念上，即远程伙伴是一个肥大单元。此外，我们有显示中枢神经系统肿瘤的新模型：即视束胶质瘤和星形细胞瘤。在目前的应用中，我们建议对视神经胶质瘤的发生有更深入的了解。此外，我们还将与同事克拉普博士和英格拉姆博士合作，研究肥大细胞在神经纤维瘤形成中的作用。

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.