Pilot Project Research Project 2

试点项目研究项目2

• 批准号: 9332105
• 负责人: ELLEN LI
• 金额: $ 9.36万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9332105
• 关键词: Address; African American; Biological; Biological Markers; Biological Models; Biopsy; Cancer Biology; Cancer Patient; Cells; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; DNA sequencing; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Early Diagnosis; Endoscopic Biopsy; Epigenetic Process; Ethnic Origin; Evaluation; Feasibility Studies; Fine needle aspiration biopsy; Future; Gene Expression; Gene Expression Alteration; Genes; Genetic; Genetic study; Genome; Genomics; Goals; Growth; Hispanic Americans; Human; Incidence; Kinetics; Laboratories; Lead; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Molecular; Not Hispanic or Latino; Obesity; Operative Surgical Procedures; Organoids; Other Genetics; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Patient Isolation; Patients; Pilot Projects; Population; Populations at Risk; Preparation; Property; Relative Risks; Research Project Grants; Risk; Sampling; Survival Rate; System; Tissue Model; Tissue Sample; Transplantation; Ultrasonography; Underrepresented Minority; Validation; Viral; Woman; Work; actionable mutation; cancer risk; carcinogenesis; caucasian American; chronic pancreatitis; cohort; diabetes risk; epigenomics; ethnic difference; genetic manipulation; high risk; human tissue; men; mortality; neoplastic cell; new therapeutic target; next generation sequencing; novel diagnostics; pancreatic cancer cells; patient population; racial and ethnic; therapy resistant; three dimensional cell culture; transcriptome; transcriptome sequencing; transcriptomics; treatment response; treatment strategy; tumor progression

Summary Pancreatic cancer holds the worst survival rate of the common malignancies, in part due to the poor response to treatments. The clinical options available to pancreatic cancer (PDA) patients are determined by the extent of disease progression, and unfortunately the vast majority of patients are ineligible for curative surgical approaches. African Americans and other underrepresented minorities have a higher incidence of, and mortality from, pancreatic cancer. In particular, African Americans have a relative risk of 1.7 for men and 1.5 for women. While Hispanic Americans do not exhibit the same level of elevated risk as African Americans, both populations are at higher risk for diabetes and obesity, two conditions associated with elevated risk for pancreatic cancer. Accordingly, our proposed work will first address the genetic and epigenetic differences that influence pancreatic cancer incidence and mortality in African American, Hispanic American, and Non-Hispanic White American patients. We hypothesize that in addition to the increased incidence of KRASG12V driver mutations observed in the African American population, there are other genetic and epigenetic differences that underlie the heightened malignancy of this disease in specific racial populations. These alterations may also influence other disease states that are associated with increased pancreatic cancer risk, such as diabetes, obesity, and chronic pancreatitis. Understanding these differences may identify new diagnostic and therapeutic targets that are more efficient at detecting and treating pancreatic cancer in these at-risk populations. To accomplish these goals, we will use a new three-dimensional, cell culture model system of pancreatic cancer progression called organoids. This culture system facilitates the rapid isolation and establishment of organoid lines from both normal and malignant human tissue. Upon isolation of patient-derived organoids from biopsies (fine needle aspirates), we will compare their genomes and transcriptomes both between racial and ethnic populations. Understanding the genetic and epigenetic counterpart to pancreatic carcinogenesis in tractable model systems will directly lead to the discovery of new biomarkers of pancreatic cancer such that early detection strategies can be developed. In addition, our findings may inform different treatment strategies and targets depending on the genomic and epigenomic landscape of the different patient populations. Given that these organoids are amenable to genetic manipulation through viral transduction or CRISPR/Cas mediated gene editing, these studies will enable iterative cycles of discovery and validation for future studies of genetic and epigenetic drivers of pancreatic cancer in under represented minorities.

总结 胰腺癌是常见恶性肿瘤中生存率最低的，部分原因是由于患者的 对治疗的反应。胰腺癌（PDA）患者可用的临床选择由以下因素决定： 疾病进展的程度，不幸的是，绝大多数患者不适合接受治疗。 手术入路非裔美国人和其他代表性不足的少数民族有较高的发病率， 胰腺癌的死亡率特别是非洲裔美国人，男性的相对风险为1.7，女性为1.5。 妇女虽然西班牙裔美国人没有表现出与非洲裔美国人相同的风险升高水平， 人群患糖尿病和肥胖症的风险更高，这两种疾病与糖尿病和肥胖症的风险升高有关。 胰腺癌因此，我们提出的工作将首先解决遗传和表观遗传差异， 影响非裔美国人、西班牙裔美国人和非西班牙裔美国人胰腺癌发病率和死亡率 白色美国患者。我们假设，除了KRASG 12 V驱动程序的发生率增加外， 在非裔美国人中观察到的突变，还有其他遗传和表观遗传差异， 是这种疾病在特定种族人群中恶性程度升高的原因。这些改变也可以 影响与胰腺癌风险增加相关的其他疾病状态，如糖尿病， 肥胖和慢性胰腺炎。了解这些差异可能会发现新的诊断和治疗方法 在这些高危人群中更有效地检测和治疗胰腺癌的靶点。 为了实现这些目标，我们将使用一种新的三维胰腺细胞培养模型系统， 癌症进展称为类器官。这种培养系统有利于快速分离和建立 来自正常和恶性人体组织的类器官系。在分离患者来源的类器官后， 活检（细针抽吸），我们将比较他们的基因组和转录组之间的种族和 民族人口。了解胰腺癌发生的遗传和表观遗传对应物 易于处理的模型系统将直接导致发现胰腺癌的新生物标志物， 可以制定早期检测策略。此外，我们的研究结果可能会为不同的治疗策略提供信息。 和靶点，这取决于不同患者群体的基因组和表观基因组景观。给定 这些类器官可以通过病毒转导或CRISPR/Cas进行遗传操作， 介导的基因编辑，这些研究将使发现和验证的迭代周期，为未来的研究， 胰腺癌的遗传和表观遗传驱动因素在代表性不足的少数民族。