Regulation of oncogenic signal transduction pathways by inositol polyphosphates

描述（由申请人提供）：项目总结：肌醇第二信使信号传导或相关通路组分的异常调节是人类癌症中最常见的异常之一，突变改变了磷酸肌醇-3激酶（PI 3 K）信号传导，代表了最好的记录改变。上游受体酪氨酸激酶、PI 3 K本身或下游靶点如AKT的激活突变或上调，以及包括PTEN在内的负调节因子的功能缺失突变表征了大量肿瘤，并且经常发生在一些最常见的中枢神经系统肿瘤中。本申请描述了由最近表征的肌醇多磷酸激酶（IPK）组成的新型肌醇信号传导途径的表征及其对人CNS癌症中细胞生长和增殖的调节。初步证据表明，IPK信号冲击典型的磷酸肌醇信号成分，包括AKT。 拟议的研究旨在描述IPK信号传导的分子作用机制，利用条件性小鼠敲除来定义其在体内的功能意义，并测试其在人类癌症模型系统中的潜在靶向作用。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Tom Curran的指导下担任讲师。候选人完成了博士学位。在所罗门H.约翰霍普金斯医学院神经科学系的斯奈德博士在所罗门H。2005-2006年的斯奈德。该奖项将支持候选人过渡到中枢神经系统癌症研究，同时建立在他的成就和发现在一个相对较新的领域的细胞信号。 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传导途径的贡献和潜在靶向作用，这种信号传导途径影响了表征良好和经常发生的癌症相关异常，特别是在中枢神经系统中。在定义癌性状态的其他调节剂时，针对癌症的多靶向方法可以在单一疗法难治的癌症中实施。

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.