Fatty Liver Disease in African Americans

肥胖是一个主要的健康问题，在美国和世界各地的患病率不断增加，并且 对非裔美国人的影响尤为严重。它可导致非酒精性脂肪肝（NAFLD）， 慢性肝炎可导致肝癌，但恶性肿瘤直到晚期才出现症状。 没有治疗选择，导致死亡率极高。另一方面，增长知识 NAFLD 导致癌症的机制途径的研究为开发早期血清提供了可能性 可以将患者分为高风险和低风险的标记物：反过来，高风险患者可以接受 肝癌监测，以便及早发现并进行根治性手术。本提案是一项协作性提案 霍华德大学 (HU) 和隆巴迪综合癌症中心 (LCCC) 的研究方法 乔治城大学发现代谢紊乱的分子和遗传特征 接受医疗护理的非裔美国人 (AA) 人群中 NAFLD 患者的机制途径 霍华德大学医院的这种情况。我们的总体目标是确定候选基因并 与 NAFLD 相关的遗传途径，寻找并填补这种极端健康的知识空白 华盛顿特区地区 AA 之间的不平等问题。这项试点研究的两位 PI——Dr. LCCC 癌症流行病学家 Christopher Loffredo 和胃肠病学家兼主席 Charles Howell 博士 霍华德大学内科博士 – 将共同指导霍华德大学的早期研究员 Ghosh 博士。博士。 戈什的专长是慢性疾病的分子遗传学。利用这些互补领域 专业知识，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：他们将参加面试，提供个人信息 和病史，并同意抽血，以便我们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，这是潜在的特征 疾病进展为肝癌。我们将积极让研究生和博士后参与研究 实验室工作。在具体目标 1 中，我们将应用基因表达分析（微阵列与 IPA 结合） 分析）揭示两组受试者的差异基因表达及其途径。在 具体目标 2 我们将通过应用高通量 TaqMan® Low 验证候选疾病标记物 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来确定这些标志物的稳健性 这种新的 TLDA 方法的稳定性、有效性、可重复性、可行性和实用性。越权行为 因此，这项研究的目标是揭示 NAFLD 可能促进的可能机制。 重要癌前途径的失调。反过来，这些知识将促进对 该少数群体的潜在治疗和预防途径。

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.