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最常见的癌症，每年仅在澳大利亚就有数千人死于胃癌。我们已经发现了一种叫做gp130的受体分子的特定基因突变，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内膜细胞不受控制生长的确切分子事件。我们将采用多种策略从分子上确定这种小鼠模型对非人类胃癌的信息提供程度。具体来说，我们将确定与疾病进展有关的基因。该项目的一个重要焦点是观察这种异常激活引发小鼠疾病的分子（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，我们将利用新的蛋白质组学技术研究我们是否可以在这些小鼠的血清中识别出一种蛋白质，这可以为我们提供小鼠是否已经发病的线索。这种蛋白在筛选人类早期无任何临床症状的胃癌中具有潜在的诊断意义。在一个相关的目标中，我们将发现可以与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者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.