Regulation of hepcidin and iron metabolism in liver disease

肝病中铁调素和铁代谢的调节

• 批准号: 8132460
• 负责人: Julia Goodnough
• 金额: $ 3.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-18 至 2012-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8132460
• 关键词: Affect; Alcoholic Liver Diseases; Cell Line; Chronic; Chronic Hepatitis C; Cirrhosis; Clinical; Concanavalin A; Deposition; Diagnosis; Disease; Disease Progression; Educational workshop; Etiology; Ferritin; GDF15 gene; Hepatic; Hepatocyte; Hepatocyte Growth Factor; Human; In Vitro; Inflammatory; Injury; Injury to Liver; Iron; Iron Overload; Liver; Liver diseases; Measurement; Minor; Molecular; Mus; PLAB Protein; Patients; Phenotype; Primary carcinoma of the liver cells; Regulation; Research; Risk; Serum; Stratification; Tissues; United States; experience; hepatoma cell; hepcidin; in vivo; injury and repair; insight; iron metabolism; liver biopsy; liver transplantation; meetings; mouse model; overexpression; peptide hormone; response; therapeutic target

DESCRIPTION (provided by the applicant): Broadly, this study proposes to investigate the molecular etiology of iron overload that accompanies chronic hepatitis C (CMC) and alcoholic liver disease. Iron overload has been shown to significantly and negatively affect the progression of these diseases; therefore, understanding etiology is important in order to gain insight into diagnosis of risk stratification and therapeutic targets. Systemic iron metabolism is regulated by the peptide hormone hepcidin, which is expressed in the liver. It is likely that the iron overload in chronic liver disease represents dysregulation of systemic iron metabolism by suppression of hepcidin in response to liver injury. Candidates for the suppressor of hepcidin include hepatocyte growth factor (HGF) and growth and differentiation factor 15 (GDF15). The regulation of hepcidin by HGF and GDF15 will be explored in vitro in primary mouse hepatocytes and human hepatoma cell lines. The effects of HGF and GDF15 with respect to hepcidin expression and iron parameters (serum iron concentration, serum ferritin, and liver tissue iron deposition) will be examined in vivo in mouse models of liver-specific HGF and GDF15 overexpression. A non-inflammatory mouse model of hepatic injury (EtOH-induced) and an inflammatory mouse model of hepatic injury (Concanavalin A-induced) will be used to investigate the effects of liver injury and repair on hepcidin expression, HGF and GDF-15. Finally, a clinical correlate will compare the serum hepcidin, HGF and GDF-15 values to chronic hepatitis C patient liver iron content (available from patient liver biopsy) and patient serum iron, ferritin measurements. In the United States patients with chronic hepatitis C (CHC) represent the largest burden of chronic hepatic disease in the United States: CHC is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation. It is increasingly evident that liver iron loading is a significant contributive factor in the progression of CHC. This study proposes to investigate the molecular causes of liver iron loading in CHC and other chronic liver disease. A minor weakness is that, to date, the candidate has not had an opportunity to attend national meeting or specialized workshops. Nor has she had an opportunity to present her research at a national meeting. Plans for these kinds of valuable experiences were not found in the application.

描述(由申请人提供)：广泛地说，这项研究建议调查伴随慢性丙型肝炎(CMC)和酒精性肝病的铁超载的分子病因学。铁超载已被证明对这些疾病的进展有显著的负面影响；因此，了解病因学对于洞察风险分层诊断和治疗目标是重要的。全身铁代谢受在肝脏表达的多肽荷尔蒙海普西丁的调节。慢性肝病中的铁超载可能是全身铁代谢失调的表现，这是通过抑制海普西丁对肝损伤的反应而实现的。肝细胞生长因子(HGF)和生长分化因子15(GDF15)是海普西丁抑制因子的候选基因。HGF和GDF15在体外对原代小鼠肝细胞和人肝癌细胞株的调节作用进行了研究。HGF和GDF15对肝脏特异性HGF和GDF15过度表达的小鼠模型的体内铁参数(血清铁浓度、血清铁蛋白和肝组织铁沉积)的影响将被检测到。我们将使用非炎症性小鼠肝损伤模型(无水乙醇诱导)和炎症性小鼠肝损伤模型(刀豆蛋白A诱导)来研究肝损伤和修复对肝组织HGF和GDF-15表达的影响。最后，一项临床相关研究将把血清中的海普西丁、HGF和GDF-15的值与慢性丙型肝炎患者的肝脏铁含量(可从患者的肝脏活检中获得)和患者的血清铁、铁蛋白的测量结果进行比较。在美国，慢性丙型肝炎(CHC)患者是美国慢性肝病的最大负担：慢性丙型肝炎是导致肝硬化、肝细胞癌和肝移植的主要原因。越来越明显的是，肝脏铁负荷是慢性丙型肝炎进展过程中的一个重要因素。本研究旨在探讨慢性丙型肝炎和其他慢性肝病患者肝脏铁负荷的分子机制。 一个小缺点是，到目前为止，候选人还没有机会参加全国会议或专门研讨会。她也没有机会在全国会议上展示她的研究成果。在申请中找不到这些有价值的体验的计划。