GENETIC MECHANISMS IN EXPERIMENTAL PANCREATIC CANCER

实验性胰腺癌的遗传机制

• 批准号: 6513323
• 负责人: ERIC P SANDGREN
• 金额: $ 31.69万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513323
• 关键词: disease /disorder model; gene expression; genetic models; genetically modified animals; laboratory mouse; laboratory rat; model design /development; neoplasm /cancer genetics; oncogenes; pancreas neoplasms; pathologic process; polymerase chain reaction; recombinase; species difference; tetracyclines

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.

描述：本文提出的研究的总体目标是 动物模型的发展，然后将被用于研究 胰腺外分泌癌的遗传学基础。胰腺癌是 在人类人口中排名第四的致命癌症。它通常是 在无法手术的阶段被诊断出来，因此患者的长期生存 非常低。加深对分子发病机制的了解 这种疾病的发生可能构成试图逆转的必要基础 预后不良。转基因动物技术的发展已经 允许建立复杂遗传病的模型，如 所选基因改变的影响可能是 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， 包括缺乏针对转基因表达的可诱导系统 以及对转基因转录调控元件的下调 在某些实验背景下，例如肿瘤进展。这个 申请中提出的研究采用了两个最新的进展 转基因方法学、四环素反应系统和 Cre/lox重组酶系统，建立胰腺外分泌模型 避免了上述限制的肿瘤，应该更多 密切反映据信导致这种情况的病因机制 人类人口中的疾病。然后，这些模型被用于 描述这种疾病的致病基础。具体目标 方法：(1)建立乳腺导管肿瘤动物模型，复制 这种癌症起源于人类的导管；(2)表征致病因素 与基因改变相关的基因改变的影响 人类胰腺外分泌癌的发生和发展；以及 (3)在物种间确定癌症的相对致病性- 相关的基因改变。转基因大鼠的最终目标代 外分泌胰腺癌模型，解决了这样一个事实，我们必须 不断地从一个物种到另一个物种进行类比推理 研究人类疾病的动物模型。这一目标的目标是 直接比较物种间的病理生理反应 相同的，精确定义的基因改变。