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

BMP抑制剂及炎症性贫血发病机制的研究

• 批准号: 8109909
• 负责人: KENNETH D BLOCH
• 金额: $ 45.87万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109909
• 关键词: Adolescent; Anemia; Anemia due to Chronic Disorder; Autoimmune Diseases; Binding; Biological; Biological Process; Blood; Blood Circulation; Bone Marrow; Bone Morphogenetic Proteins; Chemicals; Chronically Ill; Development; Diagnosis; Dietary Iron; Disease; Duodenum; Embryo; Equilibrium; Erythrocytes; Erythropoiesis; Erythropoietin; Health; Hemochromatosis; Hemoglobin; Hepatic; Hepatocyte; Homeostasis; Inflammatory; Interleukin-6; Iron; Iron Overload; Kidney Diseases; Lead; Ligands; Link; Longevity; Malignant Neoplasms; Mammalian Cell; Modeling; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Chemistry; Phosphotransferases; Plasma; Principal Investigator; Production; Protein Family; Protein Inhibition; RNA Interference; Reporting; Research; Research Personnel; Research Project Grants; Role; Screening procedure; Serum iron level result; Signal Transduction; Small Molecule Chemical Library; Specificity; Testing; Therapeutic; Vertebrates; Zebrafish; absorption; base; bone morphogenetic protein receptor type I; bone morphogenetic protein receptors; clinical application; cytokine; design; disease mechanisms study; efficacy testing; hepcidin; human disease; in vivo; inhibitor/antagonist; insight; knock-down; loss of function mutation; macrophage; metal transporting protein 1; mortality; mouse model; novel therapeutics; peptide hormone; prevent; programs; receptor; small molecule

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.

描述（由申请人提供）：炎症性贫血（AI）是癌症、肾病和自身免疫性疾病相关发病的常见诱因。 AI 通常是由炎症细胞因子表达增加导致铁调素（一种肽激素和全身铁平衡的关键调节剂）适应不良过度表达引起的。铁调素表达增加会降低血清铁水平，从而降低其对红细胞生成的可用性。最近的证据表明骨形态发生蛋白 (BMP) 在调节铁调素表达中发挥着关键作用，这提高了 BMP 拮抗剂可用于治疗 AI 的可能性。主要研究人员利用独特的体内筛选方法，确定了 Dorsomorphin 及其衍生物作为 BMP 信号传导的第一个小分子抑制剂。使用斑马鱼和小鼠的合作研究表明，这些 BMP 通路抑制剂可以减少铁调素表达并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 信号促进 AI 的机制，并开发用于治疗 AI 的 BMP 拮抗剂。将追求以下具体目标： 目标 1：鉴定炎症细胞因子诱导铁调素表达所需的 BMP 受体和配体。使用 RNAi 和 Cre/lox 方法将在培养的肝细胞中敲低 BMP 配体和受体。将使用吗啉在斑马鱼中进行补充体内研究。目标 2：利用药物化学优化 Dorsomorphin 衍生物。将开发具有增强选择性和受体亚型特异性的小分子 BMP 抑制剂。目标 3：测试小分子 BMP 拮抗剂在哺乳动物炎症性贫血模型中的功效。 dorsomorphin 衍生物增加铁和血红蛋白浓度的能力将在 AI 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 通路拮抗作用作为 AI 的治疗方法。公共健康相关性：炎症性贫血是一种困扰三分之一慢性病患者的血液疾病，它与 BMP 受体蛋白家族的意外激活有关。最近，已经发现了特异性阻断 BMP 受体激活的化合物。该研究项目旨在优化和测试这些 BMP 受体阻滞剂用于治疗炎症性贫血。