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

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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.