Pilot Project 3: Contribution of Racial Disparity towards the Early Development of Pancreatic Cancer

试点项目 3：种族差异对胰腺癌早期发展的贡献

• 批准号: 10006214
• 负责人: THOMAS D. SCHMITTGEN
• 金额: $ 11.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006214
• 关键词: 3-Dimensional; Acinus organ component; Age; Belief; Biological; California; Cell Differentiation process; Cells; Chronic Disease; Cohort Studies; Communities; Country; DNA Methylation; Data; Diagnosis; Disease; Duct (organ) structure; Ductal Epithelial Cell; Education; Epigenetic Process; Etiology; Event; Exhibits; Florida; Gene Chips; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Genome; Genotype; High Prevalence; Human; In Vitro; Incidence; Islets of Langerhans; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Metaplasia; Methylation; Molecular Genetics; Nested Case-Control Study; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Patients; Phase; Pilot Projects; Population; Process; Prospective cohort study; RNA; Race; Risk; Risk Factors; Sampling; Severity of illness; Time; Tissue Model; Tissue Sample; anticancer research; base; case control; cohort; disadvantaged population; genetic association; genome wide association study; health equity; matrigel; molecular marker; mortality; novel; pancreas development; promoter; racial disparity; socioeconomic disadvantage; transdifferentiation

ABSTRACT: PILOT PROJECT Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal cancer in the USA and is predicted to become the second most deadly cancer in the country by 2030. Blacks display an overall significantly greater age adjusted incidence and mortality rate from PDAC compared to Whites. Recognized risk factors for PDAC while at a higher prevalence in Blacks than Whites, does not account for the increased incidence and mortality from PDAC in Blacks, suggesting a biological explanation for the observed differences. The process of acinar ductal metaplasia (ADM) precedes PDAC precursor lesion formation. Since ADM is the earliest known precursor lesion for PDAC, acinar to ductal transdifferentiation is a key phase in the initiation of pancreatic cancer. We hypothesize that Blacks undergo ADM to a greater degree than Whites and that genetic as well as epigenetic factors account for this disparity. Specific Aim 1 will investigate the degree of in vitro ADM quantitatively using tissue samples from human pancreata of heathy donors obtained from pancreatic islet procurement centers. Non-islet fractions containing the primary, human pancreatic acini will be cultured and functionality will be demonstrated by inducing ADM in vitro. The duct formation doubling time and fold change in expression of acinar and ductal genes between Black and White donors will determine if ADM is enhanced in Blacks. Expression arrays will be used to identify the top genetic drivers of ADM in Blacks and Whites. Promoter DNA methylation will determine if epigenetic changes are responsible for the change in gene expression between Blacks and Whites. Specific Aim 2 will perform a genetic association study to identify SNPs in the genetic drivers of ADM using nested, case-control cohorts of PDAC data. Successful completion of this project will establish that racial disparities exist for the ability of pancreatic acini to undergo ADM. We will have also identified a gene expression signature that will characterize the ADM process by race as well as genetic and epigenetic factors that drive ADM in Blacks.

摘要：试点项目 胰腺导管腺癌 (PDAC) 是美国第四大致命癌症，预计 到 2030 年，癌症将成为美国第二大致命癌症。黑人的总体死亡率明显更高 与白人相比，PDAC 的年龄调整后发病率和死亡率。公认的 PDAC 风险因素 虽然黑人的患病率高于白人，但这并不能解释发病率和死亡率的增加 来自黑人的 PDAC，对观察到的差异提出了生物学解释。腺泡的形成过程 导管化生 (ADM) 先于 PDAC 前体病变形成。由于 ADM 是已知最早的前体 对于 PDAC 病变，腺泡到导管的转分化是胰腺癌发生的关键阶段。我们 假设黑人比白人经历 ADM 的程度更大，并且遗传和表观遗传 因素造成了这种差异。具体目标 1 将使用定量研究体外 ADM 的程度 从胰岛采购中心获得的健康捐献者的人类胰腺组织样本。 将培养含有初级人类胰腺腺泡的非胰岛部分，并对其功能进行评估 通过体外诱导 ADM 得到证实。导管形成倍增时间和腺泡表达倍数变化 黑人和白人捐赠者之间的导管基因将决定黑人的 ADM 是否得到增强。表达 阵列将用于识别黑人和白人中 ADM 的主要遗传驱动因素。启动子DNA甲基化 将确定表观遗传变化是否是黑人和黑人之间基因表达变化的原因 白人。具体目标 2 将进行遗传关联研究，以确定 ADM 遗传驱动因素中的 SNP 使用 PDAC 数据的嵌套病例对照队列。该项目的成功完成将确立种族 胰腺腺泡接受 ADM 的能力存在差异。我们还将鉴定出基因表达 特征将通过种族以及驱动的遗传和表观遗传因素来表征 ADM 过程 黑人中的 ADM。