Elucidating the Function of the NF1 Tumor Suppressor and its Effector Pathways in

描述（由申请人提供）：NF 1肿瘤抑制基因的功能缺失突变是家族性癌症综合征1型神经纤维瘤病的基础。最近，在散发性肿瘤中检测到NF 1突变，表明NF 1在人类癌症中起着更广泛的作用。本申请的总体目标是阐明NF 1失活促进肿瘤发生的分子机制。NF 1编码的蛋白，神经纤维蛋白，作为一种Ras-GT3激活蛋白（RasGAP）发挥作用。因此，Ras的失调有助于NF 1的发展;然而，神经纤维蛋白的精确分子功能仍不清楚。因此，本申请的目标是1）建立神经纤维蛋白的新功能并定义参与肿瘤发生的新效应子途径，以及2）系统地定义与Ras途径相关的NF 1肿瘤抑制网络。另一个目标是阐明NF 1突变如何参与以前未被识别的散发性肿瘤类型。为了实现这些目标，我们将使用细胞生物学，遗传学，生物化学和一些小鼠建模方法。总的来说，这些研究不仅将全面了解神经纤维蛋白如何调节Ras途径，还应该确定该途径中最关键的治疗靶点，这可能最终影响治疗开发和治疗。 公共卫生相关性：本申请的目标是研究NF 1肿瘤抑制因子的突变如何促进癌症。这项研究将提高我们对家族性癌症综合征NF 1的理解，也将提供对其他散发性癌症的见解，如脑癌和黑色素瘤。这项工作也可能影响这些疾病的治疗发展。

DESCRIPTION (provided by applicant): Loss-of-function mutations in the NF1 tumor suppressor gene underlie the familial cancer syndrome neurofibromatosis type 1. More recently NF1 mutations have been detected in sporadic tumors, suggesting that NF1 plays an even broader role in human cancer. The overall goal of this application is to elucidate the molecular mechanisms by which NF1 inactivation promotes tumorigenesis. The NF1- encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP). Accordingly, deregulation of Ras contributes to NF1 development; however, the precise molecular function of neurofibromin remains unclear. Thus the goals of this application are to 1) establish a new function of neurofibromin and define a novel effector pathway involved in tumorigenesis and 2) systematically define the NF1 tumor suppressor network as it relates to the Ras pathway. An additional goal is to elucidate how NF1 mutations participate in a previously unrecognized sporadic tumor-type. To accomplish these aims we will be using cell biological, genetic, biochemical and some mouse modeling approaches. Collectively these studies will not only provide a comprehensive understanding of how neurofibromin regulates the Ras pathway, should identify the most critical therapeutic targets in this pathway, which may ultimately impact therapeutic development and treatments. PUBLIC HEALTH RELEVANCE: The goal of this application is to investigate how mutations in the NF1 tumor suppressor promote cancer. This research will improve our understanding of the familial cancer syndrome NF1 and will also provide insight into other sporadic cancers, such as brain cancer and melanoma. This work is also likely to impact therapeutic development for these diseases.