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最常见的原因是炎性细胞因子的表达增加，导致海普西丁的非适应性过度表达，海普西丁是一种多肽激素，也是全身铁平衡的关键调节因子。海普西丁的表达增加会降低血清中铁的水平，从而减少其对红细胞生成的作用。最近的证据表明，骨形态发生蛋白(BMP)在调节海普西丁的表达中起着关键作用，这增加了BMP拮抗剂可用于治疗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多索吗啡及其衍生物是第一个BMP信号转导的小分子抑制剂。用斑马鱼和小鼠进行的合作研究表明，这些BMP途径抑制剂可以减少活体内的海普西丁的表达，提高血清铁水平，进一步支持这些小分子治疗AI的潜力。本项目旨在了解BMP信号在AI中的作用机制，并开发BMP拮抗剂用于治疗AI。目标1：确定炎症细胞因子诱导海普西丁表达所需的BMP受体和配体。BMP配体和受体将通过RNAi和Cre/lox方法在培养的肝细胞中被击倒。补充体内研究将使用吗啡在斑马鱼身上进行。目的2：用药物化学方法优化多索吗啡衍生物。小分子BMP抑制剂的开发将具有更高的选择性和受体亚型特异性。目的：检测小分子骨形态发生蛋白拮抗剂在炎症性贫血哺乳动物模型中的作用。多索吗啡衍生物增加铁和血红蛋白浓度的能力将在AI的小鼠模型中进行测试。该项目的完成将阐明BMP信号促进AI发展的机制，并验证BMP通路拮抗作为AI的一种治疗方法。与公共卫生相关：炎症贫血是一种折磨着三分之一慢性病患者的血液疾病，它与一种名为BMP受体的蛋白质家族的意外激活有关。最近，专门阻断BMP受体激活的化合物被发现。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.