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Molecular Drivers of Elevated Gallbladder Cancer Incidence in New Mexico

新墨西哥州胆囊癌发病率升高的分子驱动因素

基本信息

批准号：
10202653
负责人：
Rama Gullapalli
金额：
$ 26.34万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10202653
关键词：
Address Animal Model Archives Arkansas Automobile Driving Basic Science Bile fluid Biodistribution Bioinformatics Biological Assay Biology Bolivia Cadmium Cancer Patient Caucasians Cell Line Cells Chelating Agents Chile Chilean Cholelithiasis Chronic Clinical Collaborations Country Data Demographic Analyses Epithelial Epithelial Cells Ethnic Origin Exposure to Functional disorder Future Gallbladder Gastrointestinal tract structure Gender Geography Goals Heavy Metals Hispanics Household Human Incidence India Inductively Coupled Plasma Mass Spectrometry Inflammation Intervention Studies Libraries Link MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Malignant neoplasm of gallbladder Malignant neoplasm of gastrointestinal tract Mass Spectrum Analysis Measures Medicine Metal exposure Metals Mexican Minority Modeling Molecular Mucous Membrane Native Americans New Mexico Nutritional Operative Surgical Procedures Outcome PTGS2 gene Pathway interactions Patients Pattern Permeability Proteomics Protocols documentation Research Risk Factors Role Sampling Seminal Signal Transduction Somatic Mutation Southwestern United States Survival Rate Testing Therapeutic Intervention Time Tissues United States Universities Uranium Zinc anticancer research biliary tract cancer diagnosis cancer health disparity carcinogenesis cell motility cohort exome sequencing gallbladder carcinogenesis genetic linkage analysis innovation novel overexpression phosphoproteomics population based preventive intervention screening socioeconomic disadvantage survival outcome translational study wound healing

项目摘要

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.

项目概要：胆囊癌（GBC）是第五大常见的胃肠道恶性肿瘤，也是最常见的胃肠道恶性肿瘤。人类胆管树。美国诊断出约 4,000-5,000 例 GBC 新病例每年。生存结果惨淡，5 年生存率仅为 8%，使其成为最致命的疾病之一癌症。 GBC 具有独特的地理发病模式和全球热点。这些热点包括智利、玻利维亚、印度和美国新墨西哥州 (NM) 等国家。 GBC 发生率是 “少数族裔占多数”的美洲原住民（高出 5-8 倍）和西班牙裔（高出 2-4 倍）与居住在新墨西哥州的白人相比。 GBC 发病率差异的原因 NM 尚不清楚，我们对胆囊癌发生的理解存在严重差距。我们假设环境重金属暴露是造成 GBC 差异的关键风险因素见于新墨西哥州的少数民族。美国西南部（新墨西哥州、亚利桑那州、犹他州和内华达州）有着悠久的环境历史废弃重金属矿的遗产。这些地雷通常被发现在靠近重要地点的地方。新墨西哥州社会经济处于不利地位的美洲原住民和西班牙裔社区的数量。来证明我们的 GBC 假设，我们建议在此使用新墨西哥患者来源的胆囊上皮细胞系提议。目标 1 将使用术后胆囊样本来确定体细胞突变景观和 GBC 以种族和性别依赖性方式的关键分子驱动因素。目标 2 将确定影响新墨西哥州两种重要金属（铀和镉）在 GB 磷酸蛋白质组学中的暴露情况细胞信号传导失调。我们将特别关注金属暴露驱动的 PI3K-Akt 和 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 差异的机制解释在新墨西哥州看到。目标 3 将首次证实金属诱导 GB 上皮屏障破坏的作用引起慢性透壁炎症，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。这一基础科学提案深刻地告知了我们的实验室目前正在进行转化临床计划。最后，该提案还将提供坚定的采取基于人群的预防性筛查措施以缓解 GBC 差异的科学依据新墨西哥州的美洲原住民和西班牙裔社区。