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：
10408035
负责人：
Rama Gullapalli
金额：
$ 26.17万
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/10408035
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 Hispanic Hispanic Populations 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 hispanic community 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.

项目摘要：胆囊癌（GBC）是胃肠道第五大最常见的恶性肿瘤，也是最常见的人类胆汁树。在美国诊断出大约4,000-5,000例新GBC病例生存结果仅为5年的5年生存率，这是最致命的，这是最致命的癌症。 GBC具有与全球热点的独特地理事件模式。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发病率是在“少数族裔多数”的美洲原住民（高5-8倍）和西班牙裔（2-4倍与居住在新墨西哥州的高加索人相比。 GBC事件分布的原因 NM是未知的，在我们对胆囊癌变的理解中存在关键差距。我们假设环境重金属暴露是负责GBC分布的关键风险因素参见NM的少数民族。美国西南部（NM，AZ，UT和NV）的环境很长废弃重金属矿的遗产。这些地雷通常紧密地发现了重要的新墨西哥州的社会经济处境不利的美国原住民和西班牙裔社区数量。证明我们的 GBC假设，我们建议在此使用新墨西哥患者衍生的胆囊上皮细胞系提议。 AIM 1将使用后手术后的胆囊样品来确定躯体突变景观和 GBC的关键分子驱动因素以种族和性别依赖性方式。 AIM 2将决定新墨西哥州，铀和镉在GB磷酸蛋白质组学上的两种重要性暴露细胞信号传导失调。特别是，我们将专注于金属曝光驱动的PI3K-AKT和 MAPK信号通路改变。 AIM 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差异的机械解释在NM中看到。 AIM 3将首次确认金属引起的GB上皮屏障的破坏的作用引起慢性透壁炎症，这是胆囊癌变的众所周知的先决条件。我们的长期目标是了解使用胆囊致癌的分子机制创新的高通量生物信息学方法。这项基础科学提案深入了解我们实验室目前正在进行的转化临床计划。最后，该提案还将为公司提供科学基础以实现预防性，基于人群的筛查措施以减轻GBC差异在新墨西哥州的美国原住民和西班牙裔社区中。