Regulation of oncogenic signal transduction pathways by inositol polyphosphates

描述(由申请人提供)：项目摘要：肌醇二次信使信号或相关途径组件的异常调节是人类癌症中最常见的异常之一，其中改变肌醇肌醇-3激酶(PI3K)信号的突变是最有文献记载的变化。上游受体酪氨酸激酶、PI3K本身或下游靶标如AKT的激活突变或上调，以及包括PTEN在内的负调控因子功能突变的丧失是大量肿瘤的特征，并经常发生在一些最常见的中枢神经系统肿瘤中。目前的应用描述了一种新的肌醇多聚磷酸酶(IPKs)信号通路的特征及其对人中枢神经系统肿瘤细胞生长和增殖的调控。初步证据表明，IPK信号影响包括AKT在内的典型的肌醇磷脂信号成分。 这项拟议的研究试图描绘IPK信号的分子作用机制，利用有条件的小鼠基因敲除来确定它们在体内的功能意义，并在人类癌症模型系统中测试它们的潜在靶向。这项拟议的研究将在费城儿童医院和宾夕法尼亚大学的神经外科进行，候选人在汤姆·柯伦的指导下担任导师。这位候选人于2005-2006年在约翰霍普金斯医学院所罗门·H·斯奈德的神经科学系完成了他的博士培训。该奖项将支持候选人过渡到中枢神经系统癌症研究，同时建立在他在一个相对较新的细胞信号领域的成就和发现的基础上。 相关性：这项拟议的研究解决了一种新的、最近表征的细胞信号通路对表征良好且经常发生的癌症相关异常的影响和潜在靶向，尤其是在中枢神经系统。在定义癌症状态的额外调节者时，可以对单一疗法无效的癌症实施多靶点方法。

DESCRIPTION (provided by applicant): Project Summary: Aberrant regulation of inositide second messenger signaling or associated pathway components is one of the most prevalent abnormalities in human cancers with mutations altering phosphoinositide-3 kinase (PI3K) signaling representing the best documented alterations. Activating mutations or upregulation of upstream receptor tyrosine kinases, PI3K itself, or downstream targets such as AKT, as well as loss of function mutations of negative regulators including PTEN characterize a large number of tumors and occur frequently in some of the most common central nervous system tumors. The current application describes the characterization of a novel inositide signaling pathway comprised of the recently characterized inositol polyphosphate kinases (IPKs) and their regulation of cell growth and proliferation in human CNS cancers. Preliminary evidence suggests IPK signaling impinges upon canonical phosphoinositide signaling components including AKT. The proposed research seeks to delineate the molecular mechanisms of action of IPK signaling, define their functional significance in vivo utilizing conditional mouse knockouts, and test their potential targeting in human cancer model systems. The proposed research will be conducted at the Department of Neurosurgery at the Children's Hospital of Philadelphia and University of Pennsylvania where the candidate holds the position of instructor under the mentorship of Tom Curran. The candidate completed his Ph.D. training in the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins Medical School under Solomon H. Snyder in 2005-2006. The award will support the candidate's transition into central nervous system cancer research while building on his accomplishments and discoveries in a relatively new field of cell signaling. Relevance: The proposed research addresses the contribution and potential targeting of a novel, recently characterized cell signaling pathway impinging on well characterized and oft occurring cancer-associated abnormalities, particularly in the central nervous system. In defining additional regulators of the cancerous state a multitargeted approach towards cancer can be implemented in cancers refractory to monotherapies.