Mechanism of tumor suppression by p27

马修·费罗是一位医学肿瘤学家，他的研究兴趣集中在细胞周期基因的作用、癌症的发展以及细胞生长的控制上。这一奖项允许Fero博士加深我们对细胞周期抑制(CKI)基因p27kip1抑制肿瘤的理解，同时在他的职业生涯中从一名指导研究员的职位过渡到一名独立的研究员。这项拟议中的研究利用了费罗博士在操纵小鼠胚胎过程中获得的技能，在实验室小鼠身上产生了针对感兴趣基因的突变，这些突变仅限于特定的组织。这些新的基因突变将与明确的诱导致癌小鼠模型和基因表达分析相结合，以确定p27的肿瘤抑制机制及其在肿瘤发生中的生化作用。通过将细胞周期基因突变局限于脑下垂体或胸腺的小鼠，将确定p27kipI是否可以独立于周围细胞或组织的因素的影响，以一种自主的方式诱导这些组织中的腺瘤和淋巴瘤。同样，对发生在小鼠体内的肠道肿瘤、淋巴瘤和前列腺癌的分析将确定这些肿瘤是否也是以一种自主的方式出现的。将在每个模型系统中进一步确定p27抑制肿瘤的机制，并将表征改变的基因表达和细胞周期蛋白功能的模式。如果p27突变以细胞非自主方式导致肿瘤，确定p27缺陷细胞和肿瘤细胞之间的信号通路将是很重要的。然后，治疗剂可以针对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.