Fatty Liver Disease in African Americans

非裔美国人的脂肪肝

• 批准号: 10468978
• 负责人: Somiranjan Ghosh
• 金额: $ 8.31万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468978
• 关键词: Acute; Address; Affect; African American; African American population; Age; Area; Biological; Biological Markers; Biopsy; Blood; Candidate Disease Gene; Caring; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Chronic Hepatitis; Cirrhosis; Clinical; Collaborations; Comprehensive Cancer Center; Control Groups; Country; Coupled; Curative Surgery; Data; Diagnosis; Disease; Disease Marker; Disease Progression; District of Columbia; Enrollment; Epidemiologist; Epidemiology; Ethnic group; Extrahepatic; Fatty Liver; Fibrosis; Fostering; Funding; Future; Gastroenterologist; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Health; Hepatic; Image; Inflammation; Internal Medicine; Intervention Studies; Interview; Keratin; Knowledge; Laboratories; Lead; Light; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Measurement; Measures; Medical; Medical History; Mentors; Metabolic; Metabolic syndrome; Minority Groups; Mission; Molecular Genetics; Molecular Profiling; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obesity; Obesity Epidemic; Outcome; Pathway Analysis; Pathway interactions; Patients; Pilot Projects; Postdoctoral Fellow; Prevalence; Prevention; Reproducibility; Research; Research Personnel; Risk; Sampling; Secure; Sensitivity and Specificity; Serology; Serum Markers; Solid; Source; Testing; Time; Tissue-Specific Gene Expression; United States; Universities; University Hospitals; Viral hepatitis; Work; anticancer research; base; biomarker discovery; biomarker validation; chronic liver disease; collaborative approach; comorbidity; comparative; complement C3 precursor; density; disorder risk; doctoral student; epidemiology study; fatty liver disease; genetic signature; health disparity; high risk; indexing; minority health disparity; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; patient stratification; predictive modeling; preventive intervention; recruit

Obesity is a major health concern that is increasing in prevalence in the U.S. and worldwide, and disproportionately affects African Americans. It can lead to non-alcoholic fatty liver disease (NAFLD), which in turn can lead to liver cancer via chronic hepatitis, but the malignancy is asymptomatic until late stage when curative options are unavailable, leading to extremely high mortality. On the other hand, increasing knowledge of the mechanistic pathways by which NAFLD leads to cancer offers the possibility to develop early serum markers that can stratify patients into those at higher and lower risk: in turn, higher risk patients can undergo liver cancer surveillance to identify it early enough for curative surgery. The present proposal is a collaborative approach for research at Howard University (HU) and the Lombardi Comprehensive Cancer Center (LCCC) at Georgetown University to discover the molecular and genetic signatures of perturbed metabolic and mechanistic pathways in NAFLD patients in an African–American (AA) population receiving medical care for this condition at Howard University Hospital. Our overall objective is to identify candidate genes and genetic pathways associated with NAFLD, to find and fill the knowledge gaps of this extreme health disparity issue among AA around the Washington DC region. The two PIs of this pilot study – Dr. Christopher Loffredo, a cancer epidemiologist at LCCC, and Dr. Charles Howell, a gastroenterologist and Chair of Internal Medicine at Howard University – will co-mentor Dr. Ghosh, an early stage investigator at HU. Dr. Ghosh's expertise is molecular genetics of chronic diseases. Leveraging these complementary areas of expertise, we propose to use pilot funding from this P20 proposal to enroll 50 NAFLD patients (cases) and 50 matched controls at Howard University: they will participate in an interview to provide information on personal and medical history, and will agree to a blood draw that will allow us to assess differences in levels of gene expression in cancer-relevant mechanistic pathways (e.g. inflammation) that are potential signatures of disease progression towards liver cancer. We will actively involve graduate and post-doctoral students in the laboratory work. In Specific Aim 1 we will apply a gene expression analysis (microarray coupled with IPA analysis) to divulge the differential gene expressions and their pathways in the two groups of subjects. In Specific Aim 2 we will validate the candidate disease markers by applying high-throughput TaqMan® Low Density Arrays (TLDA). We will validate the precise panel of genes within the particular biological pathways and we will integrate clinical, epidemiologic and laboratory data to identify the robustness of these markers towards stability, validity, reproducibility, feasibility and utility of this new TLDA approach. The overreaching goal of this research is, therefore, to shed new light on possible mechanisms by which NAFLD may contribute to the dysregulation of important pre-cancer pathways. In turn, such knowledge will foster the identification of potential avenues for treatment and prevention for this minority population.

肥胖是一个主要的健康问题，在美国和世界范围内的流行率正在增加， 对非裔美国人的影响不成比例。它可以导致非酒精性脂肪肝（NAFLD）， 转可导致肝癌通过慢性肝炎，但恶性肿瘤是无症状的，直到晚期， 没有治疗选择，导致极高的死亡率。另一方面，增加知识 NAFLD导致癌症的机制途径提供了开发早期血清的可能性， 可以将患者分为高风险和低风险的标记物：反过来，高风险患者可以经历 肝癌监测，以尽早发现它的治疗手术。目前的建议是一个合作 霍华德大学（HU）和伦巴第综合癌症中心（LCCC）的研究方法， 乔治敦大学发现的分子和遗传特征的扰动代谢和 接受以下医疗护理的非裔美国人（AA）人群中NAFLD患者的机制途径： 这种情况在霍华德大学医院。我们的总体目标是确定候选基因， 与NAFLD相关的遗传途径，以发现和填补这种极端健康的知识空白， 在华盛顿地区的AA之间的差异问题。本初步研究的两名PI-Dr. LCCC的癌症流行病学家Christopher Loffredo和胃肠病学家兼主席Charles豪厄尔博士 霍华德大学内科学教授-将共同指导HU的早期研究者Ghosh博士。博士 Ghosh的专长是慢性疾病的分子遗传学。利用这些互补领域， 我们建议使用P20提案中的试点资金招募50名NAFLD患者（病例）和50名 霍华德大学的匹配对照：他们将参加一次访谈，提供个人信息 和病史，并同意抽血，这将使我们能够评估基因水平的差异， 在癌症相关机制途径（例如炎症）中的表达，这些途径是 疾病进展为肝癌。我们将积极让研究生和博士后学生参与 实验室工作。在具体目标1中，我们将应用基因表达分析（与IPA偶联的微阵列 分析）揭示两组受试者基因表达的差异及其途径。在 具体目标2我们将通过应用高通量TaqMan® Low 密度阵列（TLDA）。我们将验证特定生物途径中的精确基因组 我们将整合临床、流行病学和实验室数据， 对这种新的TLDA方法的稳定性，有效性，再现性，可行性和实用性。过度延伸 因此，本研究的目的是阐明NAFLD可能的机制 重要的癌前通路的失调。反过来，这种知识将促进识别 为这一少数群体提供治疗和预防的潜在途径。