BMP inhibitors and the study of disease mechanisms in anemia of inflammation

描述（由申请人提供）：炎症性贫血（AI）是癌症、肾脏疾病和自身免疫性疾病相关发病率的常见因素。AI通常是由炎症细胞因子的表达增加导致hepcidin（一种肽激素和系统铁平衡的关键调节剂）的不适应过度表达引起的。hepcidin表达增加降低血清铁水平，降低其红细胞生成的有效性。最近的证据表明骨形态发生蛋白（BMP）在调节hepcidin表达中起关键作用，这增加了BMP拮抗剂用于治疗AI的可能性。利用一种独特的体内筛选方法，主要研究人员已经确定dorsomorphin及其衍生物是BMP信号传导的第一个小分子抑制剂。利用斑马鱼和小鼠进行的合作研究表明，这些BMP通路抑制剂可以降低hepcidin的表达，提高体内血清铁水平，进一步支持这些小分子治疗AI的潜力。该项目旨在了解BMP信号对人工智能的作用机制，并开发用于治疗人工智能的BMP拮抗剂。目标1：鉴定炎症细胞因子诱导hepcidin表达所需的BMP受体和配体。利用RNAi和Cre/lox方法在培养的肝细胞中敲除BMP配体和受体。补充的体内研究将在斑马鱼中使用morpholinos进行。目的2：利用药物化学优化dorsomorphin衍生物。小分子BMP抑制剂将被开发出来，具有更高的选择性和受体亚型特异性。目的3：检测小分子BMP拮抗剂对炎症性贫血动物模型的疗效。dorsomorphin衍生物增加铁和血红蛋白浓度的能力将在小鼠AI模型中进行测试。该项目的完成将阐明BMP信号促进AI发展的机制，并验证BMP通路拮抗剂作为AI的治疗方法。公共卫生相关性：三分之一的慢性病患者患有炎症性贫血，这与BMP受体家族蛋白的不必要激活有关。最近，已经发现了特异性阻断BMP受体激活的化合物。本研究项目旨在优化和测试这些BMP受体阻滞剂治疗炎症性贫血。

DESCRIPTION (provided by applicant): Anemia of inflammation (AI) is a frequent contributor to the morbidity associated with cancer, kidney disease, and autoimmune diseases. AI is most often caused by an increased expression of inflammatory cytokines leading to maladaptive over-expression of hepcidin, a peptide hormone and critical regulator of systemic iron balance. Increased hepcidin expression decreases serum levels of iron, reducing its availability for erythropoiesis. Recent evidence has suggested a pivotal role for bone morphogenetic proteins (BMPs) in regulating hepcidin expression, raising the possibility that BMP antagonists could be used for treating AI. Utilizing a unique in vivo screening approach, the principal investigators have identified dorsomorphin and its derivatives as the first small molecule inhibitors of BMP signaling. Collaborative studies using zebrafish and mice have shown that these BMP pathway inhibitors can reduce hepcidin expression and boost serum iron levels in vivo, further supporting the potential of these small molecules for treating AI. This project seeks to understand the mechanisms by which BMP signals contribute to AI and to develop BMP antagonists for treating AI. The following Specific Aims will be pursued: AIM 1: To identify the BMP receptors and ligands that are required for the induction of hepcidin expression by inflammatory cytokines. BMP ligands and receptors will be knocked down in cultured hepatocytes using RNAi and Cre/lox approaches. Complementary in vivo studies will be performed in zebrafish using morpholinos. AIM 2: To optimize dorsomorphin derivatives using medicinal chemistry. Small molecule BMP inhibitors will be developed with enhanced selectivity and receptor-subtype specificity. AIM 3: To test the efficacy of small molecule BMP antagonists in mammalian models of the anemia of inflammation. The ability of dorsomorphin derivatives to increase iron and hemoglobin concentrations will be tested in mouse models of AI. Completion of this project will clarify the mechanisms by which BMP signals contribute to the development of AI and validate BMP pathway antagonism as a therapeutic approach for AI. PUBLIC HEALTH RELEVANCE: Anemia of Inflammation, a blood condition afflicting a third of all chronically-ill patients, has been linked to unwanted activation of a family of proteins called BMP receptors. Recently, chemical compounds that specifically block activation of BMP receptors have been discovered. This research project seeks to optimize and test these BMP receptor blockers for treating Anemia of Inflammation.