Exploring the Role of Mitochondrial Fission in Pancreatic Tumorigenesis

 描述（由申请人提供）：超过90%的胰腺癌在Ras基因中存在突变，但鉴定靶向突变Ras蛋白的药物已被证明是困难的。因此，至关重要的是，我们了解突变Ras引起的生化和生理变化，以便我们可以确定更适合药理学干预的药物靶点。为此，Ras驱动的胰腺肿瘤的特征在于线粒体功能的变化。线粒体是细胞内存在的细胞器，负责产生能量并提供细胞增殖所需的构建模块。我们已经发现了Ras蛋白的活性与控制线粒体融合和分裂的细胞机制之间的新联系。最近的研究表明，线粒体融合和分裂的调控对线粒体功能有很大的影响。我们假设，改变线粒体融合和裂变的平衡是突变Ras促进过度增殖所必需的，线粒体融合和裂变机制可能是胰腺癌的一个有吸引力的药物靶点。在目的1中，我们的目标是阐明Ras诱导的线粒体分裂在一系列患者来源的胰腺癌细胞系中的生理后果。在目标二和三中，我们的目标是使用两种互补的和生理相关的胰腺导管腺癌小鼠模型来测试胰腺肿瘤生长对线粒体分裂的需求，并探索线粒体分裂机制是否可能是一个可行的药物靶点。这些目标的完成将使我们更好地了解线粒体功能在胰腺癌中的重要作用，并使我们能够确定治疗干预的新靶点。

 DESCRIPTION (provided by applicant): Over 90% of pancreatic cancers harbor a mutation in the Ras gene, yet identifying drugs that target the mutant Ras protein have proven difficult. Therefore, it is critical that we understand the biochemical and physiological changes elicited by mutant Ras so that we can identify drug targets more amenable to pharmacological intervention. To that end, Ras-driven pancreatic tumors are characterized by changes in mitochondrial function. The mitochondria are organelles present within the cell that are responsible for generating energy and providing the building blocks required for cellular proliferation. We have uncovered a novel link between the activity of Ras proteins and the cellular machinery that controls the fusion and fission of the mitochondria. Recent research indicates that the regulation mitochondrial fusion and fission greatly impacts mitochondrial function. We hypothesize that altering the balance of mitochondrial fusion and fission is required for mutant Ras to promote excess proliferation and that the mitochondrial fusion and fission machinery might represent an attractive drug target for pancreatic cancer. In aim 1, our goal is to elucidate the physiological consequences of Ras- induced mitochondrial fission in a series of patient-derived pancreatic cancer cell lines. In aims two and three, our goal is to use two complementary and physiologically relevant mouse models of pancreatic ductal adenocarcinoma to test the requirement of mitochondrial fission for pancreatic tumor growth and explore whether the mitochondrial fission machinery might be a viable drug target. Completion of these aims will give us a better understanding of the important role mitochondrial function plays in pancreatic cancer and allow us to identify novel targets for therapeutic intervention.