Mechanism of tumor suppression by p27

Matthew Fero是一名医学肿瘤学家，他的研究兴趣主要集中在细胞周期基因在癌症发展和细胞生长控制中的作用。该奖项允许Fero博士进一步了解细胞周期抑制剂（CKI）基因p27kip1的肿瘤抑制作用，同时在他的职业生涯中从一名受指导的研究员转变为一名独立研究者。拟议的研究利用Fero博士在操纵小鼠胚胎方面获得的技能，在实验室小鼠中产生特定于感兴趣基因和特定组织的突变。这些新的基因突变将与明确的小鼠诱导致癌模型和基因表达分析相结合，以确定p27的抑瘤机制及其在肿瘤发生中的生化作用。通过培养具有局限于垂体或胸腺的细胞周期基因突变的小鼠，将确定p27kipI是否能够自主地在这些组织中诱导腺瘤和淋巴瘤，即不受周围细胞或组织因素的影响。同样，对小鼠肠道肿瘤、淋巴瘤和前列腺肿瘤进行分析，这些肿瘤是p27基因突变的遗传嵌合体，将确定这些肿瘤是否也以自主方式出现。在每个模型系统中，p27抑制肿瘤的机制将被进一步定义，基因表达和细胞周期蛋白功能的改变模式将被表征。如果p27突变以细胞非自主方式引起肿瘤，那么确定在p27缺陷细胞和肿瘤细胞之间起作用的信号通路将是重要的。然后治疗剂可以靶向细胞周期蛋白或介导癌症发展的细胞内分子。

Matthew Fero is a medical oncologist with research interests which focus on the role of cell cycle genes the development of cancer and in the control of cell growth. This award permits Dr. Fero to further our understanding of tumor suppression by the cell cycle inhibitor (CKI) gene p27kip1, while making a transition in his career from the position of a mentored researcher to an independent investigator. The proposed studies utilize the skills Dr. Fero has acquired in the manipulation of the mouse embryo to produce mutations in laboratory mice which are specific both to genes of interest and confined to particular tissues. These novel gene mutations will then be combined with well defined murine models of induced carcinogenesis and gene expression analysis to define the mechanism of tumor suppression of p27 and it's biochemical effects in tumorigenesis. By developing mice which harbor cell cycle gene mutations confined to the pituitary or thymus it will be determined whether the p27kipI can induce adenomas and lymphomas in these tissues in an autonomous fashion, that is independent of the influence of factors from surrounding cells or tissues. Likewise analysis of intestinal tumors, lymphomas and prostate tumors developing in mice which are genetic mosaics for p27 gene mutations will determine whether these tumors also arise in an autonomous fashion. The mechanism of tumor suppression by p27 will be further defined in each model system and the patterns of altered gene expression and cell cycle protein function will be characterized. If p27 mutations cause tumors in a cell non-autonomous fashion it will be important to determine the signaling pathway which acts between the p27 deficient cell and the neoplastic cell. Therapeutic agents may then be targeted at either the cell cycle proteins or the intracellular molecules which mediate cancer development.