Cincinnati Center of Neurofibromatosis Research

为了响应国家神经疾病和中风研究所的RFA，我们建议建立辛辛那提神经纤维瘤病研究中心。我们的目标是识别和治疗NF1功能丧失导致的周围神经肿瘤的信号通路。为了实现这一目标，我们召集了三个小组，用遗传学、分子和细胞方法攻击NF1肿瘤，进行临床前试验。在项目1中，George Thomas和Sara Kozma将研究RAF、PI3K和PKA信号通路在NF1发展中的作用，这些信号通路的作用是否通过S6K1的结构性激活来介导，以及新型药物抑制剂在细胞培养和小鼠中对NF1模型的影响。与John Perentesis密切合作，该小组将启动药物的组合研究，首先是基于细胞的活性分析，然后是作为人类临床研究的翻译模型的异种移植。在项目2中，Nancy Ratner使用这些相同的模型和新的小鼠品系来测试新的假设，即NF1中明显的非RAS信号实际上可以归因于RAS相关蛋白TC21，并使用项目1中测试的相同药物来阻止细胞迁移。TC21信号级联和迁移将作为新疗法的靶点进行测试。在项目3中，David Largespada将在小鼠身上使用一种创新的转座子插入突变策略来筛选修改周围神经肿瘤发生的基因。已识别的基因将存在于代表下一代治疗策略目标的信号通路中。所有项目都使用管理核心(Ratner，PI)、小鼠异种移植核心(Timothy Cripe，PI)和病理核心(Tilat Rizvi，PI)。我们的长期目标是将研究成果转化为患者的治疗方法。辛辛那提儿童医院拥有一家杰出的儿科NF1诊所，其数据库中有800多名患者，参与了正在进行的NF1临床试验，并参与了一个新的OOD NF临床联盟项目。它也是儿科抗癌药物开发的领先中心，也是NCI儿科第一阶段联盟的成员。这些项目汇聚了一个世界级的研究小组，在一个可以促进临床试验的环境中识别和分层用于NF1治疗的药物。

In response to an RFA from the National Institute of Neurological Disorders and Stroke, we propose to establish a Cincinnati Center for Neurofibromatosis Research. Our goal is to identify and therapeutically target signaling pathways that underlie peripheral nerve tumors resulting from NF1 loss of function. To accomplish this goal we have brought together three groups to attack NF1 tumors with genetic, molecular and cellular approaches to preclinical testing. In Project 1, George Thomas & Sara Kozma will investigate the contribution of the RAF, PI3K and PKA signaling pathways in the development of NF1, whether the effects of these pathways are mediated through constitutive activation of S6K1, and the impact of novel pharmacological inhibitors in models of NF1 in cell culture and in the mouse. Working closely with John Perentesis this group will initiate combinatorial studies of drugs first in cell based viability assays, then in xenografts as translational models for human clinical studies. In Project 2, Nancy Ratner uses these same models and new mouse strains to test the novel hypothesis that apparently non-Ras signaling in NF1 can actually be attributed to the Ras-related protein TC21, and use the same drugs tested in Project 1 for their ability to block cell migration. TC21 signaling cascades and migration will be tested as targets for novel therapies. In Project 3, David Largaespada will use an innovative transposon insertional mutagenesis strategy in mice to screen for genes that modify peripheral nerve tumorigenesis. Identified genes will lie in signaling pathways that represent next generation targets for therapeutic strategies. All projects use an Administrative Core (Ratner, PI), a Mouse Xenograft Core (Timothy Cripe, PI) and a Pathology Core (Tilat Rizvi, PI). Our long-term goal is to translate research findings into patient therapies. Cincinnati Children's Hospital has an outstanding pediatric NF1 clinic with over 800 patients in its database, has participated in ongoing NF1 clinical trials, and participates in a new OOD NF Clinical Consortium project. It is also a leading center for pediatric anticancer drug development and a member of the NCI's Pediatric Phase I Consortium. Together these projects bring together a world class group of investigators to identify and stratify drugs for use in NF1 treatment, in an environment that can facilitate clinical trials.