Molecular Drivers of Elevated Gallbladder Cancer Incidence in New Mexico

项目摘要： 胆囊癌（GBC）是第五常见的胃肠道恶性肿瘤，并且是最常见的胃肠道恶性肿瘤。 人体胆道系统在美国大约有4000 - 5000例新的GBC病例被诊断出来 每年。生存结果令人沮丧，5年生存率仅为8%，使其成为最致命的疾病之一 癌的GBC具有独特的地理发病模式，具有全球热点。这些热点包括 智利、玻利维亚、印度和美国的新墨西哥州等国家。GBC发病率为 在“少数-多数”的美洲原住民（高5-8倍）和西班牙裔（2-4倍）中异常高 与生活在新墨西哥州的白人相比，GBC发病率差异的原因 NM是未知的，在我们对胆囊癌发生的理解中存在关键的差距。 我们假设环境重金属暴露是导致GBC差异的关键危险因素 在NM的少数民族中看到。美国西南部（NM，AZ，UT和NV）有长期的环境保护。 废弃的重金属矿。这些地雷通常位于重要的 新墨西哥州一些社会经济上处于不利地位的美洲原住民和西班牙裔社区。来证明我们 GBC假说，我们建议使用新墨西哥州患者来源的胆囊上皮细胞系， 提议目标1将使用手术后胆囊样本来确定体细胞突变景观， GBC的关键分子驱动因素，以种族和性别依赖的方式。目标2将决定 暴露于新墨西哥州的两种重要金属，铀和镉，对GB磷酸蛋白质组学 细胞信号失调特别是，我们将重点关注金属暴露驱动的PI 3 K-Akt的作用， MAPK信号通路改变。目标3将确定镉和铀暴露对 胆囊上皮屏障破坏和伤口愈合作为GBC差异的机制解释 在NM看到的目的3将首次证实金属诱导的GB上皮屏障破坏的作用 引起慢性透壁性炎症，这是众所周知的胆囊癌发生的先决条件。 我们的长期目标是了解胆囊癌发生的分子机制， 创新的高通量生物信息学方法。这一基础科学建议深刻地告知了 我们实验室目前正在进行的转化临床计划。最后，这一建议还将提供一个坚定的 科学基础，使预防性，基于人口的筛查措施，以减轻GBC的差距看到 在新墨西哥州的美洲原住民和西班牙裔社区。

Project Summary: Gallbladder Cancer (GBC) is the fifth most common malignancy of the GI tract and the most common in the human biliary tree. Approximately 4,000-5,000 new cases of GBC are diagnosed in the United States annually. Survival outcomes are dismal with only ~8% 5-year survival rate, making it one of the deadliest cancers. GBC has a distinct geographical incidence pattern with global hotspots. These hotspots include countries like Chile, Bolivia, India and the state of New Mexico (NM) in the United States. GBC incidence is abnormally high among the “minority-majority” Native Americans (5-8 fold higher) and Hispanics (2-4 fold higher) compared to Caucasians living in New Mexico. The reasons underlying GBC incidence disparities in NM is unknown and there are critical gaps in our understanding of gallbladder carcinogenesis. We postulate environmental heavy metal exposure is the key risk factor responsible for GBC disparities seen among minorities of NM. The southwestern United States (NM, AZ, UT and NV) has a long environmental legacy of abandoned heavy metal mines. These mines are usually found in close proximity to a significant number of socio-economically disadvantaged Native American and Hispanic communities of NM. To prove our GBC hypothesis, we propose the use of New Mexican patient derived gallbladder epithelial cell lines in this proposal. Aim 1 will use post-surgical gallbladder samples to determine the somatic mutational landscapes and key molecular drivers of GBC in an ethnicity and gender dependent manner. Aim 2 will determine the impact of exposures of two metals of significance in New Mexico, uranium and cadmium, on the GB phosphoproteomic cell signaling dysregulation. In particular, we will focus on the role of metal exposure driven PI3K-Akt and MAPK signaling pathway alterations. Aim 3 will determine the effects of cadmium and uranium exposure on gallbladder epithelial barrier disruption and wound healing as a mechanistic explanation of GBC disparities seen in NM. Aim 3 will confirm, for the first time, the role of metal induced disruption of the GB epithelial barrier causing chronic transmural inflammation which is a well-known prerequisite of gallbladder carcinogenesis. Our long-term goal is to understand the molecular mechanisms of gallbladder carcinogenesis using innovative, high-throughput bioinformatics approaches. This basic science proposal deeply informs the translational clinical initiatives currently underway in our lab. Finally, this proposal will also provide a firm scientific basis to enable preventative, population based screening measures to alleviate GBC disparities seen in Native American and Hispanic communities of New Mexico.