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:10629366
- 负责人:
- 金额:$ 26.03万
- 依托单位:
- 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:
- 关键词:AddressAnimal ModelArchivesArkansasAutomobile DrivingBasic ScienceBile fluidBiodistributionBioinformaticsBiological AssayBiologyBoliviaCadmiumCancer PatientCaucasiansCell LineCellsChelating AgentsChileChileanCholelithiasisChronicClinicalCollaborationsCountryDataDemographic AnalysesDisparityEpithelial CellsEpitheliumEthnic OriginExposure toFunctional disorderFutureGallbladderGastrointestinal tract structureGenderGeographyGoalsHeavy MetalsHispanicHispanic PopulationsHouseholdHumanIncidenceIndiaInductively Coupled Plasma Mass SpectrometryInflammationIntervention StudiesLibrariesLinkMAP Kinase GeneMAPK Signaling Pathway PathwayMalignant NeoplasmsMalignant neoplasm of gallbladderMalignant neoplasm of gastrointestinal tractMass Spectrum AnalysisMeasuresMedicineMetal exposureMetalsMexicanMinorityModelingMolecularMucous MembraneNative AmericansNew MexicoNutritionalOutcomePIK3CG genePTGS2 genePathway interactionsPatientsPatternPermeabilityProteomicsProtocols documentationResearchRisk FactorsRoleSamplingSeminalSignal TransductionSomatic MutationSouthwestern United StatesSurvival RateTestingTherapeutic InterventionTimeTissuesUnited StatesUniversitiesUraniumZincanticancer researchbiliary tractcancer diagnosiscancer health disparitycarcinogenesiscell motilityclinical translationcohortexome sequencinggallbladder carcinogenesisgenetic linkage analysishispanic communityinnovationnoveloverexpressionphosphoproteomicspopulation basedpreventive interventionscreeningsocioeconomic disadvantagesurvival outcometranslational studywound 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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Rama Gullapalli', 18)}}的其他基金
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
- 批准号:
10202653 - 财政年份:2020
- 资助金额:
$ 26.03万 - 项目类别:
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
- 批准号:
10408035 - 财政年份:2020
- 资助金额:
$ 26.03万 - 项目类别:
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