Stopping the Start: Understanding PanIN Initiation and Progression

描述(由申请人提供)：目前的提案概述了一个研究培训计划，在该计划中，我将在约翰·霍普金斯大学史蒂文·利奇博士的指导下，对胰腺癌(Panin)早期病变的启动和进展进行复杂的研究。超过80%的胰腺癌患者存在Kras基因突变，胰腺癌的确切起源细胞尚未定义。因此，我们建议发展一种形成Panin的“下一代”小鼠模型，在该模型中，我们用融合到Kras的绿色荧光蛋白(GFP)标记细胞，以成像胰腺中经历重组并表达激活Kras的细胞。我们将激活成年小鼠胰腺腺泡或导管内的Kras。有了GFP：KRAS融合，我们将能够在致癌Kras表达激活后的特定时间点识别、可视化和分离细胞，从而实现了一系列新颖的实验，在这些实验中，细胞对胰腺Kras激活的反应甚至可以在Panin病变形成之前进行研究，并且具有前所未有的空间和时间分辨率。使用这一新的方法，我们将检验以下假设：首先，即使在形态Panin形成开始之前，单个胰腺上皮细胞就以基因表达、增殖和形态的进行性变化对致癌Kras的表达做出反应；其次，腺泡细胞和导管细胞可能在这些反应中表现出差异；第三，慢性胰腺炎影响对Kras的反应，最后，了解这些最早的反应将允许药物终止Panin的启动和进展。 公共卫生相关性：胰腺癌是一种极其致命的癌症，确诊后两年存活率不到5%。我们建议研究胰腺癌的最早起始事件，以确定这种致命疾病的治疗或诊断的新途径。我们认为这些研究与更好地理解导管或腺泡细胞对致癌的Kras激活的最早反应有关。

DESCRIPTION (provided by applicant): The current proposal outlines a research training program in which I will pursue sophisticated studies of the earliest lesions in pancreatic cancer (PanIN) initiation and progression under the mentorship of Dr. Steven Leach at Johns Hopkins University. Greater than 80% of pancreatic cancer patients have Kras mutations and the exact cell of origin for pancreatic cancer has not been defined. Therefore, we propose to develop a "next generation" mouse model of PanIN formation, in which we label cells with green flourescent protein (GFP) fused to Kras to image cells in the pancreas that have undergone recombination and express activated Kras. We will activate Kras in the acinar or ductal compartment of adult mouse pancreas. With the GFP:Kras fusion, we will be able to identify, visualize and isolate cells at discreet time points following activation of oncogenic Kras expression, empowering a series of novel experiments in which the cellular response to pancreatic Kras activation can be studied even prior to the formation of PanIN lesions, and with unprecedented spatial and temporal resolution. Using this novel approach, we will test the following hypotheses: First, that even prior to the onset of morphologic PanIN formation, individual pancreatic epithelial cells respond to oncogenic Kras expression with progressive changes in gene expression, proliferation, and morphology; second, that acinar and ductal cells may exhibit differences in these responses; third, that chronic pancreatitis influences the response to Kras, and finally, that understanding these earliest responses will allow the pharmacologic termination of PanIN initiation and progression. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is an incredibly lethal form of cancer with a less than 5% chance of two year survival after diagnosis. We are proposing to study the earliest initiating events of pancreatic cancer to identify novel pathways for the treatment or diagnosis of this lethal disease. We believe these studies are relevant to better understand the earliest responses of ductal or acinar cells to oncogenic Kras activation.