JAK/STAT PATHWAY CONTROL OF CELL COMPETITION DURING DEVELOPMENT.

描述（由申请人提供）：控制细胞竞争的分子机制在治疗生长缺陷、癌症生物学和再生医学方面具有巨大的发展潜力。细胞竞争是一种质量控制机制，以确保只有“最适合”的细胞才能为成年有机体做出贡献。它与早期的 癌症的阶段，其中代谢率升高的转化细胞接管了野生型细胞的领域。 细胞竞争是沿着相邻细胞群的界面诱导的， 不同的代谢率：具有较高生长率的细胞（赢家）以较低生长率的细胞（输家）为代价进行繁殖。在果蝇中的工作已经表明，dmyc（在许多肿瘤中重排的人类癌基因c-myc的唯一果蝇同源物）的过度表达赋予细胞赢家地位，并且这与诱导从头核糖体生物发生强烈相关。 该提案中的工作表明，JAK/STAT信号通路的持续激活导致细胞成为以牺牲其失败者邻居为代价而生长的赢家，而通路活性的降低赋予“失败者”状态，导致消除。 四个JAK或七个STAT的过度激活导致几种人类癌症。 在果蝇中有一个JAK和一个STAT（称为Stat 92 E），这种遗传冗余的缺乏使果蝇成为解决该途径在细胞竞争中的作用的理想系统。 本申请中的初步数据表明，Stat 92 E不通过dMyc发挥作用，反之亦然。此外，与dMyc不同，超活性Stat 92 E不诱导核糖体生物合成。然而，表达过度活跃的Stat 92 E或升高的dMyc的获胜者导致位于几个细胞直径之外的失败者死亡。 这些结果表明，激活的Stat 92 E是一个超级竞争者，并强烈表明，Stat 92 E和dMyc独立运作，并收敛于共同的靶基因编码的可溶性蛋白质，导致死亡的失败者。 本申请的广泛、长期目标是确定JAK/STAT途径活性增加的获胜者所使用的竞争分子机制。 将使用全基因组表达谱来鉴定与对照相比在具有过度活跃的Stat 92 E的获胜者中具有改变的表达的靶基因（目的1）。 果蝇翼盘中的克隆生长测定将用于产生表达高度活跃的Stat 92 E但缺乏候选基因的获胜者，然后确定这些细胞是否仍然可以杀死位于几个细胞直径之外的失败者（Aim 2）。 这项申请的目标与NICHD的使命非常相关，其中之一是“了解生长和发育”，因为这项提案中的实验可能会发现正常生长所需的基因，这些基因可能会被转化细胞吸收。 公共卫生相关性：由于进化，jak和stat基因在其他生物中以非常相似的形式存在，例如果蝇。果蝇是一种优秀的遗传器官，多年来一直被用于研究实验室，并在识别和表征基本生物过程的关键基因方面取得了巨大成功。 我们的研究旨在阐明JAK/STAT通路如何调节果蝇的细胞竞争。

DESCRIPTION (provided by applicant): The molecular mechanisms controlling cell competition hold great potential for advances in treating growth deficiencies, in cancer biology and in regenerative medicine. Cell competition is a quality-control mechanism to insure that the only the "fittest" cells contribute to the adult organism. It shares many properties with the early stages of cancer, in which transformed cells with elevated metabolic rates take over a field of wild-type cells. Cell competition is induced along the interface of adjacent cell populations that differ in metabolic rates: cells with the higher growth rate (winners) reproduce at the expense of those with the lower one (losers). Work in Drosophila has shown that over-expression of dmyc, the sole fly homolog of the human oncogene c-myc that is re-arranged in many tumors, confers winner status on cells, and this is strongly correlated with inducing de novo ribosome biogenesis. The work in this proposal shows that sustained activation of the JAK/STAT signaling pathway causes cells to become winners that grow at the expense of their loser neighbors, while reduction in pathway activity imparts "loser" status, resulting in elimination. Hyper-activation of the four JAKs or seven STATs causes several human cancers. There is a single JAK and a single STAT (called Stat92E) in Drosophila, and this lack of genetic redundancy makes Drosophila an ideal system in which to address the role of this pathway in cell competition. The preliminary data in this application show that Stat92E does not function through dMyc and vice versa. Furthermore, unlike dMyc, hyper-active Stat92E does not induce ribosome biogenesis. However, winners expressing hyper-active Stat92E or elevated dMyc cause the death of losers located several cell diameters away. These results demonstrate that activated Stat92E is a super-competitor and strongly suggest that Stat92E and dMyc operate independently and converge on common target genes encoding soluble proteins that cause death in losers. The broad, long-term objectives of this application are to determine the molecular mechanisms of competition used by winners with increased activity of the JAK/STAT pathway. Genome-wide expression profiling will be used to identify target genes that have altered expression in winners with hyper-active Stat92E as compared to controls (Aim 1). A clonal growth assay in the Drosophila wing disc will be used to generate winners that express hyper-active Stat92E but lack the candidate gene and then to determine if these cells can still kill losers located several cell diameters away (Aim 2). The goals of this application are extremely pertinent to the mission of the NICHD, one of which is "learning about growth and development," as the experiments in this proposal will likely uncover genes required for normal growth and that may be co-opt by transformed cells. PUBLIC HEALTH RELEVANCE: Due to evolution, jak and stat genes exist in very similar forms in other organisms, such as the fruit fly Drosophila. The fruit fly is an excellent genetic organis that has been used for many years in research laboratories and with great success to identify and characterize genes critical for basic biological processes. Our study is designed to eludicate how the JAK/STAT pathway regulates cell competition in Drosophila.