Pilot Project 1

试点项目1

• 批准号: 10302611
• 负责人: Rafat Ali Siddiqui
• 金额: $ 4.27万
• 依托单位: VIRGINIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302611
• 关键词: African American; Anti-Inflammatory Agents; Antineoplastic Agents; Biological Assay; Blueberries; Cancer Center; Cancer Etiology; Cell Line; Cessation of life; Chronic; Data; Data Set; Databases; Development; Dietary Component; Disease; Ethnic Origin; Evaluation; Exhibits; Gene Expression; Genes; Ginger; Growth; Hepatitis C; Hepatitis C virus; IFI6 gene; ISG15 gene; Incidence; Inflammation; Inflammatory; Interferon Type I; Interferons; Knowledge; Malignant Neoplasms; Measures; Mediating; Molecular; Molecular Profiling; Not Hispanic or Latino; Nutraceutical; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Phosphotransferases; Pilot Projects; Play; Preventive; Primary carcinoma of the liver cells; Property; RNA analysis; Race; Research Training; Risk Factors; Role; Running; STAT1 gene; STAT2 gene; Sampling; Signal Pathway; Signal Transduction; Survival Rate; The Cancer Genome Atlas; Therapeutic; Tissue Banks; Tissue-Specific Gene Expression; Toxic effect; Training Programs; Translating; Universities; Virginia; Virulence; anti-cancer; base; black patient; cancer health disparity; caucasian American; chemotherapy; cytokine; dietary; differential expression; effective therapy; efficacy evaluation; established cell line; gain of function; genetic signature; innovation; insight; loss of function; mortality; novel; overexpression; patient derived xenograft model; prevent; racial disparity; response; side effect; targeted treatment; transcriptome sequencing; tumor; tumorigenesis

PILOT PROJECT 1: PROJECT SUMMARY Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality running parallel to its incidence. Lack of effective treatment for advanced HCC calls for insights into the molecular pathogenesis of HCC and development and evaluation of novel, targeted therapeutic strategies. For HCC patients, there is a statistically significant increase in incidence and mortality and a decrease in 5-year survival rates in African American (AA)/Black patients compared to non-Hispanic (white) patients. There is a gap of knowledge in our understanding of the molecular mechanism underlying the HCC racial disparity between AA/Black and white patients. Analysis of RNA-sequencing (RNA-Seq) data in the TCGA database and RNA-Seq on HCC tumor samples revealed that in both datasets the only pathway that showed statistically significant activation in AA/Black patients is the type I interferon (IFN-I) signaling pathway. This pathway is activated by Hepatitis C virus (HCV) infection, a major risk factor for HCC. Correction of the differential gene expression data based on HCV status still identified activation of IFN-I signaling pathway in AA/Black HCC patients indicating that the observed findings in AA/Black patients are independent of HCV status. HCC is a disease of chronic inflammation and IFN-Is function as pro- inflammatory and immunosuppressive cytokines, establishing the rationale for studying them. We hypothesize that persistent activation of the IFN-I signaling pathway might be a key determinant of racial disparity in AA/Black HCC patients, and even if IFN-I-inducible genes (ISGs) are induced in response to HCV infection in AA/Black patients their expression is maintained—contributing to HCC development and virulence. In this study, the role of a 4-ISG signature in regulating HCC in white and AA/Black patients will be systematically analyzed using HCC patient-derived xenograft (PDX) cell lines and the efficacy of dietary anti-inflammatory compounds in inhibiting them will be evaluated. The proposed studies will help develop a targeted therapeutic approach for AA/Black HCC patients thus having both mechanistic and therapeutic significance and innovation. Successful completion of the proposed studies will create new avenues for effective treatment of scores of AA/Black HCC patients for whom currently no effective treatment option is available.

试点项目1：项目摘要 肝细胞癌（HCC）是一种高度致命的疾病，死亡率与事件平行。缺乏 高级HCC的有效治疗需要深入了解HCC和发育的分子发病机理 以及对针对性的理论策略的评估。对于HCC患者，具有统计学意义 非裔美国人（AA）/黑色的发病率和死亡率增加以及5年生存率的降低 患者与非西班牙裔（白人）患者相比。我们的理解有一定的知识 AA/黑白患者之间HCC种族差异的基础分子机制。分析 TCGA数据库中的RNA - 序列（RNA-SEQ）数据和HCC肿瘤样品上的RNA-Seq显示，在 这两个数据集在AA/黑色患者中表现出统计学意义的唯一途径是I型 干扰素（IFN-I）信号通路。该途径被丙型肝炎病毒（HCV）感染激活，这是主要风险 HCC的因素。基于HCV状态的差异基因表达数据的校正仍鉴定出激活 AA/黑色HCC患者中的IFN-I信号通路，表明AA/黑色患者观察到的发现 独立于HCV状态。 HCC是一种慢性炎症和IFN-IS的疾病 炎症和免疫抑制细胞因子，建立了研究它们的基本原理。我们假设 IFN-I信号通路的持续激活可能是AA/Black种族差异的关键决定者 HCC患者，即使IFN-I-诱导的基因（ISG）也因AA/黑色的HCV感染而诱导 保持患者的表达 - 归因于HCC发育和病毒。在这项研究中，角色 在确定白色和AA/黑色患者HCC中的4-ISG签名将使用HCC系统分析 患者衍生的特征（PDX）细胞系和饮食抗炎化合物抑制效率 他们将进行评估。拟议的研究将有助于开发针对AA/黑色的有针对性的治疗方法 HCC患者因此具有机械性和治疗意义和创新。成功完成 在拟议的研究中，将创建新的途径，以有效治疗数十位AA/黑色HCC患者 目前没有有效的治疗选择。