Regulation of oncogenic signal transduction pathways by inositol polyphosphates

项目概述：肌肽第二信使信号或相关通路组分的异常调节是人类癌症中最普遍的异常之一，其突变改变了磷酸肌肽-3激酶（PI3K）信号，代表了最具文献记录的改变。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在内的负调节因子的功能缺失突变是大量肿瘤的特征，并且在一些最常见的中枢神经系统肿瘤中经常发生。目前的申请描述了一种新的肌醇信号通路的特征，该信号通路由最近表征的肌醇多磷酸激酶（IPKs）组成，以及它们对人类中枢神经系统癌症细胞生长和增殖的调节。初步证据表明，IPK信号会影响包括AKT在内的典型磷酸肌苷信号成分。

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.