Regulation of hepcidin and iron metabolism in liver disease

描述（由申请人提供）：总的来说，本研究旨在研究伴随慢性丙型肝炎（CMC）和酒精性肝病的铁超载的分子病因。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，了解病因是重要的，以便深入了解危险分层的诊断和治疗目标。全身铁代谢由肽激素hepcidin调节，该激素在肝脏中表达。慢性肝病中的铁超载很可能代表了在肝损伤反应中通过抑制hepcidin来调节全身铁代谢的失调。候选的hepcidin抑制因子包括肝细胞生长因子（HGF）和生长与分化因子15 （GDF15）。HGF和GDF15对hepcidin在小鼠原代肝细胞和人肝癌细胞系中的调控作用将在体外进行研究。HGF和GDF15对hepcidin表达和铁参数（血清铁浓度、血清铁蛋白和肝组织铁沉积）的影响将在肝脏特异性HGF和GDF15过表达的小鼠模型中进行体内检测。我们将使用非炎症性肝损伤小鼠模型（etoh诱导）和炎症性肝损伤小鼠模型（Concanavalin A诱导）来研究肝损伤和修复对hepcidin表达、HGF和GDF-15的影响。最后，临床相关性将比较血清hepcidin， 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，肝铁负荷是CHC进展的一个重要促进因素。本研究旨在探讨CHC及其他慢性肝病患者肝脏铁负荷的分子原因。

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.