Biomarker for Hepatocellular Carcinoma

肝细胞癌的生物标志物

• 批准号: 7632128
• 负责人: Jack R Wands
• 金额: $ 23.82万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-17 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632128
• 关键词: Animal Model; Antibodies; Binding; Biodistribution; Biological Assay; Biological Markers; Cell Surface Proteins; Cell surface; Chromatography; Chronic; Chronic Hepatitis C; Cirrhosis; Cities; Clinical Research; Detection; Development; Diabetes Mellitus; Diagnosis; Disease; Early Diagnosis; Enzymes; Epidemic; Genes; Growth; Health Professional; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Human; Immunoassay; Immunoglobulin G; Incidence; Insulin Resistance; Lead; Length; Life Expectancy; Liver; Liver diseases; Malignant Epithelial Cell; Mass Spectrum Analysis; Measures; Mixed Function Oxygenases; Modeling; Monoclonal Antibodies; Mus; N-terminal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Patients; Primary carcinoma of the liver cells; Proteins; Reagent; Recombinant Proteins; Risk Factors; Role; Screening procedure; Serum; Techniques; Time; Tumor Tissue; Two-Dimensional Gel Electrophoresis; United States; anti-IgG; base; cell motility; expression cloning; improved; nonalcoholic steatohepatitis; novel; novel marker; outcome forecast; prognostic; prospective; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): Human hepatocellular carcinoma (HCC) is one of the most serious complications of chronic liver disease and cirrhosis. Even more disturbing is the observation that the average life expectancy from the time of diagnosis is approximately eight to ten months. The incidence of HCC has begun to increase in the United States principally due to the contribution of chronic hepatitis C (HCV) infection. In addition, with the obesity epidemic including Type II diabetes and insulin resistance, the emergence of non-alcoholic steatohepatitis (NASH) has begun to assume a larger role in the pathogenesis of this devastating disease due to the development of cirrhosis, a risk factor for HCC. More recently, there is widespread concern among health care professionals regarding the increase in HCC and the lack of optimal screening techniques that lead to or contribute to early diagnosis and treatment in the hope of improving the prognosis of this almost uniformly fatal disease. Thus, the purpose of this proposal is to validate a new marker that may be useful in the early diagnosis of HCC. In this regard, we have identified by monoclonal antibody (mAb) binding and expression cloning, a cell surface protein marker that is enhanced in HCC tumors. The gene encoding for this protein has been cloned and molecularly identified as aspartyl (asparaginyl) (¿-hydroxylase (HAAH) which appears to be highly expressed in most (>90%) hepatitis B (HBV) and HCV related HCC. Furthermore, this protein appears to be present in serum of such patients. Thus, we have established immunoassays to detect C and N terminal fragments as well as full length HAAH in serum using recombinant proteins as standards. Because this enzyme is expressed on the cell surface, we have recently developed human scFv and IgG antibodies directed against the various region of the molecule. These reagents will be used in biodistribution studies to target tumors in murine models of human HCC. Evidence will be presented to support the hypothesis that HAAH gene is a novel biomarker for HCC since expression appears to be highly associated with the pathogenesis of the disease. We plan to do the following. Specific Aim 1. Validate HAAH as a biomarker for HCC. Specific Aim 2. Further characterize human scFv fragments and IgG anti-AAH antibodies. It is likely that these new mAb based assays will be useful for the early detection of HCC and human anti-HAAH antibodies may be employed as targeting reagents for the specific detection of HCC in the liver.

描述（由适用提供）：人肝细胞癌（HCC）是慢性肝病和肝硬化最严重的并发症之一。更令人不安的是，从诊断开始的平均预期寿命约为八到十个月。 HCC的事件已开始在美国开始增加，这主要是由于慢性丙型肝炎（HCV）感染的贡献。此外，随着包括II型糖尿病和胰岛素抵抗在内的肥胖症流行，非酒精性脂肪性肝炎（NASH）的出现已经开始在这种毁灭性疾病的发病机理中扮演更大的作用，这是由于Cirrhosis的发展，这是HCC的危险因素。最近，医疗保健专业人员对HCC的增加以及缺乏导致或有助于早期诊断和治疗的最佳筛查技术的关注，以期改善这种几乎统一致命疾病的预后。这是该提案的目的是验证一种新标记，该标记可能在早期诊断HCC中有用。在这方面，我们通过单克隆抗体（MAB）结合和表达克隆鉴定，这是一种细胞表面蛋白标记，在HCC肿瘤中增强。该蛋白质编码的基因已被克隆并分子鉴定为香氨酸（白凝素）（天冬氨酸）（�-羟化酶（HAAH），似乎在大多数（> 90％）丙型肝炎（> 90％）乙型肝炎（HBV）（HBV）和HCV相关的HCC中都具有高度表达。使用重组蛋白作为标准的血清中的末端碎片和全长，因为这种酶在细胞表面上表达，我们最近开发了针对分子的各个区域的人类SCFV和IgG抗体。对于HCC，我们计划进行以下特定目标，因为表达与疾病的发病机理高度相关。这些新的基于mAb的新测定可能对早期检测HCC很有用，并且可以将人类抗HAAH抗体作为靶向试剂，以特异性检测肝脏中的HCC。