GENETIC MECHANISMS IN EXPERIMENTAL PANCREATIC CANCER

描述：本文提出的研究的总体目标是 动物模型的开发，然后将用于检查 外分泌胰腺癌的遗传基础 胰腺癌是一种 是人类第四致命的癌症 它通常 在不能手术的阶段就被诊断出来， 异常低。增加对分子发病机制的了解 这种疾病的可能形成一个必要的基础，试图扭转 预后不佳。 转基因动物技术的发展， 允许建立复杂遗传疾病的模型， 选择性遗传改变的影响可能是 与体内特定的病理生理后果相关。 然而，转基因方法有几个技术限制， 包括缺乏用于靶向转基因表达的诱导系统 以及转基因转录调控元件的下调 在某些实验背景下，如肿瘤进展。 的 该申请中提出的研究采用了两项最新进展， 转基因方法、四环素反应系统和 cre/lox重组酶系统构建胰腺外分泌模型 避免上述限制并且应该更多的肿瘤 密切反映了被认为是导致这种情况的病因学机制， 人类的疾病。 这些模型用于 描述疾病的发病基础。 具体目标 （1）建立乳腺导管瘤动物模型， 这种癌症在人类中的导管起源;（2）表征致病性 基因改变的影响，已经与 人类外分泌胰腺癌的发展和进展;以及 (3)确定不同物种之间癌症的相对致病性 相关的基因突变。 转基因大鼠的最终目标代 外分泌胰腺癌的模型，解决了一个事实，我们必须 当使用时，不断地从一个物种类比到另一个物种。 研究人类疾病的动物模型。 这一目标的目的是 直接比较，种属之间， 相同的精确定义的基因改变

DESCRIPTION: The overall objective of the studies proposed herein is the development of animal models that will then be used to examine the genetic basis of exocrine pancreatic cancer. Pancreatic cancer is the fourth most lethal cancer in the human population. It is typically diagnosed at an inoperable stage so that long term patient survival is exceptionally low. Increased understanding of the molecular pathogenesis of this disease may form a necessary foundation for attempts to reverse the poor prognosis. The development of transgenic animal technology has permitted the establishment of models of complex genetic diseases like cancer for which the effects of selected genetic alterations can be correlated with specific pathophysio-logical consequences in vivo. However, the transgenic approach has had several technical limitations, including lack of inducible systems for targeting transgene expression and the down regulation of transgene transcriptional regulatory elements in certain experimental contexts, such as neoplastic progression. The studies proposed in the application employ two recent advances in transgenic methodology, the tetracycline responsive system and the cre/lox recombinase system, to create models of exocrine pancreatic neoplasia that avoid the limitation described above and that should more closely reflect the etiological mechanisms believed to cause this disease in the human population. These models are then used to characterize the pathogenetic basis of the disease. The specific aims are: (1) establish animal models of ductal neoplasia that reproduce the ductal origin of this cancer in humans; (2) characterize the pathogenic effects of genetic alterations that have been associated with the development and progression of exocrine pancreatic cancer in humans; and (3) determine, between species, the comparative pathogenicity of cancer- related genetic alterations. The final aim generation of transgenic rat models of exocrine pancreatic cancer, addresses the fact that we must continually reason by analogy from one species to another when using animal models to study human disease. The goal of this aim is to directly compare, between species, the pathophysiological responses to identical, precisely defined genetic alterations.