BMP Signaling and Iron Metabolism

描述(由申请人提供)： 申请者建议的项目是为在转化生长因子-β超家族信号和铁代谢领域的学术医学和基础科学研究职业生涯做准备。研究将在麻省理工学院丹尼斯·布朗博士的实验室进行。铁的稳态受到严格的调控，为生长和生存提供这种关键元素，但也是为了防止铁过量的毒性。血凝素(Hemojuvelin，HJV)是最近发现的一种基因突变，在大多数青少年血色沉着症病例中发生突变，这是一种严重的铁超载疾病。虽然HJV的功能尚不清楚，但在HJV变异者中，HJV的海普西丁水平受到抑制，这表明HJV正向调节海普西丁的表达。海普西丁是一种由肝脏分泌的可溶性蛋白质，是全身铁平衡的关键调节因子，其水平与肠道铁摄取和巨噬细胞和肝细胞释放铁呈负相关。初步研究结果表明：1)HJV是斥力引导分子(RGM)家族的一员，是增强骨形态发生蛋白(BMP)信号转导的辅助受体；2)HJV基因突变导致铁超载削弱其BMP信号转导能力；3)BMP-2上调了HJV-/-肝细胞中Hepsidin的表达；4)在Hjv-/-肝细胞中，BMP-2诱导的Hp表达被钝化。这些数据揭示了BMP信号通路和铁代谢之间的新联系，并提示了HJV突变导致血色病的机制：HJV功能障碍减少了BMP-2信号，从而降低了海普西丁的表达。本研究的目的是：1)研究BMP-2调控细胞色素表达的分子机制，包括BMP-2与其他已知的细胞因子，如炎症介质、HFE、TfR2、铁超载和贫血之间的相互作用；2)确定BMP-2信号通过HJV在体内对细胞内的细胞色素表达、铁蛋白表达、血清铁和组织铁水平的影响；3)确定其他转化生长因子-β超家族成员对细胞色素表达和铁代谢的影响。相关性：铁平衡失调是一个严重的公共卫生问题，影响着全球10多亿人。这项建议旨在研究一种新的调控途径，它似乎在铁平衡中发挥关键作用。希望这项工作能为血色素沉着症等铁超载障碍和慢性病贫血等缺铁障碍提供新的治疗策略。

DESCRIPTION (provided by applicant): The applicant proposes a program to prepare for a career in academic medicine and basic science research in the field of TGF-beta superfamily signaling and iron metabolism. Research will be conducted in the laboratory of Dr. Dennis Brown at MGH. Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. Hemojuvelin (HJV), was recently identified as the gene mutated in most cases of juvenile hemochromatosis, a severe disorder of iron overload. Although the function of HJV is unknown, hepcidin levels are depressed in persons with HJV mutations, suggesting that HJV positively regulates hepcidin expression. A soluble protein secreted by the liver, hepcidin is a critical regulator of systemic iron homeostasis whose levels are inversely correlated with iron uptake from the intestine and release from macrophages and hepatocytes. Preliminary data is presented that 1) HJV, a member of the repulsive guidance molecule (RGM) family, is a co-receptor that enhances bone morphogenetic protein (BMP) signaling; 2) mutations in HJV which cause iron overload impair its BMP signaling ability; 3) BMP-2 upregulates hepcidin expression; 4) BMP-2 induction of hepcidin expression is blunted in Hjv-/- hepatocytes. These data reveal a novel link between the BMP signaling pathway and iron metabolism and suggest a mechanism by which HJV mutations cause hemochromatosis: HJV dysfunction decreases BMP-2 signaling, thereby lowering hepcidin expression. This proposal aims to: 1) Characterize the molecular mechanisms by which BMP-2 regulates hepcidin expression, including the interaction between this pathway and other known modulators of hepcidin expression such as inflammatory mediators, HFE, TfR2, iron overload, and anemia; 2) Determine the effects of BMP-2 signaling via HJV in vivo on hepcidin expression, ferroportin expression, serum iron, and tissue iron levels; 3) Determine the role of other TGF- beta superfamily members on hepcidin expression and iron metabolism. Relevance: Disorders of iron balance represent a significant public health problem affecting over a billion people worldwide. This proposal aims to investigate a novel regulatory pathway, which appears to play a key role in iron balance. It is hoped that this work will provide clues leading to new treatment strategies for disorders of iron overload such as hemochromatosis and disorders of iron deficiency such as anemia of chronic disease.