Cell Proliferation Mediated by Tsc1/Tsc2

描述(申请人提供)：对细胞增殖和生长调控的研究对我们理解发育生物学和肿瘤发生很重要。这项拟议研究的长期目标是研究调节细胞增殖和生长的分子机制。为了解决这个问题，研究人员将在果蝇发育中的想象组织中分析TSC1和TSC2肿瘤抑制基因以及与它们相互作用的基因。TSC1或TSC2的突变会导致遗传性疾病--结节性硬化症。这种疾病发生在6000名新生儿中的1/6000，其特征是多器官的良性肿瘤，称为错构瘤。TSC1和TSC2在功能上从苍蝇到人类都是保守的。研究人员此前已经证明，TSC1和TSC2共同作用于胰岛素/PI3K/Akt信号通路，位于Akt下游和S6K上游。TSC1、TSC2和该途径的其他上游成分影响细胞的增殖和生长，而S6K只影响细胞的生长。TSC1和TSC2调控细胞增殖的机制尚不清楚。研究人员建议研究TSC1和TSC2调控细胞增殖的机制。具体地说，研究人员建议通过进行遗传修饰物筛选和使用微阵列来识别受TSC1/TSC2调控的基因来识别TSC1/TSC2相互作用的基因。然后，研究人员将选择几个TSC1/TSC2相互作用的基因，并进一步表征这些已识别的候选基因与TSC1/TSC2之间的相互作用以及它们在细胞增殖调控中的作用。提交K08导师奖的申请是为了使候选人能够在发育和分子遗传学方面获得必要的教学和科学培训。最终目标是独立研究人类疾病的分子机制，并利用模式生物开发有针对性的治疗策略。

DESCRIPTION (provided by applicant): Studies on the regulation of cell proliferation and growth are important to our understanding of developmental biology and tumorigenesis. The long-term goal of the proposed research is to investigate the molecular mechanisms that regulate cell proliferation and growth. In order to address this question, the investigators will analyze the Tsc1 and Tsc2 tumor suppressor genes as well as genes interacting with them in the developing imaginal tissues of Drosophila melanogaster. Mutations in either TSC1 or TSC2 result in a hereditary disease - tuberous sclerosis. The disease occurs in 1/6000 births and is characterized by benign neoplasms known as hamartomas, in multiple organs. Tsc1 and Tsc2 are functionally conserved from flies to humans. The investigators have previously shown that Tsc1 and Tsc2 function together in the Insulin/PI3K/Akt signaling pathway, downstream of Akt and upstream of S6K. Tsc1, Tsc2, and other upstream components of the pathway affect both cell proliferation and growth, however S6K only affects cell growth. The mechanism by which Tsc1 and Tsc2 regulate cell proliferation is not yet known. The investigators propose to investigate the mechanism by which cell proliferation is regulated by Tsc1 and Tsc2. Specifically, the investigators propose to identify Tsc1/Tsc2 interacting genes by performing genetic modifier screens and by using microarray to identify genes regulated by Tsc1/Tsc2. The investigators will then select several Tsc1/Tsc2 interacting genes and further characterize the interaction between these identified candidate genes and Tsc1/Tsc2 as well as their role in the regulation of cell proliferation. This application for the mentored K08 award is submitted so as to enable the candidate to gain necessary didactic and scientific training in developmental and molecular genetics. The eventual goal is to independently investigate molecular mechanisms underlying human disease and develop targeted therapeutic strategy utilizing model organisms.