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: 7545262
• 负责人: Julia Goodnough
• 金额: $ 3.06万
• 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/7545262
• 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; MCC protocol; Measurement; Minor; Molecular; Mus; PLAB Protein; Patients; Phenotype; Primary carcinoma of the liver cells; Protein Overexpression; Regulation; Research; Risk; Serum; Stratification; Tissues; United States; experience; hepatoma cell; hepcidin; in vivo; injury and repair; insight; iron metabolism; liver biopsy; liver transplantation; mouse model; 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（由申请方提供）：广泛而言，本研究旨在研究慢性丙型肝炎（CMC）和酒精性肝病伴发的铁过载的分子病因学。铁超载已被证明对这些疾病的进展有显着的负面影响;因此，了解病因是重要的，以便深入了解风险分层和治疗目标的诊断。全身性铁代谢受肽激素铁调素调节，该肽激素在肝脏中表达。慢性肝病中的铁过载可能代表了响应于肝损伤的铁调素抑制引起的全身铁代谢失调。铁调素抑制因子的候选物包括肝细胞生长因子（HGF）和生长和分化因子15（GDF 15）。将在体外在原代小鼠肝细胞和人肝癌细胞系中探索HGF和GDF 15对铁调素的调节。将在肝特异性HGF和GDF 15过表达的小鼠模型中体内检查HGF和GDF 15对铁调素表达和铁参数（血清铁浓度、血清铁蛋白和肝组织铁沉积）的影响。将使用肝损伤的非炎性小鼠模型（EtOH诱导的）和肝损伤的炎性小鼠模型（伴刀豆球蛋白A诱导的）来研究肝损伤和修复对铁调素表达、HGF和GDF-15的影响。最后，临床相关性将比较血清铁调素、HGF和GDF-15值与慢性丙型肝炎患者肝铁含量（可从患者肝活检获得）和患者血清铁、铁蛋白测量值。在美国，慢性丙型肝炎（CHC）患者是美国慢性肝病的最大负担：CHC是肝硬化、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CHC进展的重要贡献因素。本研究旨在探讨慢性丙型肝炎及其他慢性肝病患者肝脏铁负荷的分子原因。 一个小缺点是，迄今为止，候选人没有机会参加国家会议或专门讲习班。她也没有机会在全国会议上介绍她的研究。在申请书中没有找到这类宝贵经验的计划。