Validation of Stat3 as a therapeutic target in diseases arising from its inappropriate activation by gp130 cytokines

胃癌是西方世界第三大流行癌症，仅在澳大利亚每年就有数千人死亡。我们发现了一种叫做gp130的受体分子的特殊基因突变，这种突变导致了小鼠胃癌的形成。我们现在的目标是了解这种突变导致胃粘膜细胞不受控制的生长的确切分子事件。我们将采用一些策略，以建立分子的程度，这种小鼠模型是胃癌人类的信息。特别地，我们将确定参与疾病进展的基因。该项目的一个重要焦点是观察异常激活触发小鼠疾病的分子（称为Stat3）是否可以为干预该疾病提供未来的药理学靶点。与CIB的专业知识类似，我们将研究新的蛋白质组学技术，我们可以在这些小鼠的血清中鉴定一种蛋白质，这可以给我们一个线索，小鼠是否已经发展成疾病。这种蛋白可能是潜在的诊断价值，在未来的筛选人类胃癌，在其早期阶段通常是没有任何临床症状。在一个相关的目标中，我们将找出可以与Stat3基因合作的基因，这是使新生小鼠存活所必需的。我们的建议结合了两位研究人员在信号转导方面的专业知识，并且该基因可能是确保Stat3在许多不同器官中触发生理反应而不是病理反应的重要决定因素。

Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.