BMP Signaling and Iron Metabolism

描述（由申请人提供）： 申请人提出了一个计划，以准备在学术医学和基础科学研究领域的TGF-β超家族信号和铁代谢的职业生涯。研究将在MGH的Dennis Brown博士的实验室进行。铁稳态受到严格调节，以提供这种生长和生存的关键元素，但要防止铁过量的毒性。血幼素（Hemojuvelin，HJV）是近年来发现的在青少年血色素沉着症（一种严重的铁超负荷疾病）中发生突变的基因。虽然HJV的功能是未知的，hepcidin水平在HJV突变的人被压抑，表明HJV积极调节hepcidin的表达。铁调素是一种由肝脏分泌的可溶性蛋白质，是全身性铁稳态的关键调节剂，其水平与肠铁摄取以及巨噬细胞和肝细胞释放的铁呈负相关。初步数据显示，1）HJV，排斥性引导分子（RGM）家族的成员，是增强骨形态发生蛋白（BMP）信号传导的共受体; 2）HJV中导致铁过载的突变损害其BMP信号传导能力; 3）BMP-2上调hepcidin表达; 4）BMP-2对hepcidin表达的诱导在HGV-/-肝细胞中减弱。这些数据揭示了BMP信号通路和铁代谢之间的新联系，并提出了HJV突变引起血色素沉着症的机制：HJV功能障碍降低BMP-2信号传导，从而降低铁调素表达。该提案旨在：1）表征BMP-2调节铁调素表达的分子机制，包括该途径与其他已知的铁调素表达调节剂如炎症介质、HFE、TfR 2、铁过载和贫血之间的相互作用; 3）确定其他TGF-β超家族成员对铁调素表达和铁代谢的作用。相关性：铁平衡失调是一个严重的公共卫生问题，影响到全世界10亿多人。该提案旨在研究一种新的调节途径，该途径似乎在铁平衡中起关键作用。希望这项工作将提供线索，导致新的治疗策略的铁超载的疾病，如血色素沉着症和缺铁性疾病，如贫血的慢性疾病。

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.