Hepcidin is a recently described hormone that plays a critical role in iron metabolism. Hepcidin targets ferroportin for degradation thereby reducing export of iron from macrophages and enterocytes. Induction of hepcidin production by inflammatory mediators reduces iron availability for erythropoiesis leading to the anemia of inflammation. The PIs have combined their expertise in chemical biology and disease modeling to investigate how bone morphogenetic protein (BMP) signaling regulates hepcidin and ferroportin expression. The team's accomplishments include discovery of the first small molecule inhibitors of BMP signaling and demonstration that these inhibitors can treat anemia of inflammation in animal models. More recently, it has become apparent that the BMP-hepcidin-ferroportin signaling pathway can contribute to inflammatory diseases not typically attributed to abnormalities of iron homeostasis, including atherosclerosis. In this renewal application, the PIs propose to continue using genetics and chemical biology to study iron homeostasis, with a new focus on the role of hepcidin-ferroportin signaling in macrophage function and the role of this signaling pathway in health and disease.
Three aims are proposed.
In Aim 1, the PIs will take advantage of facile genetic and pharmacological manipulations in transparent zebrafish to characterize the role of hepcidin-ferroportin signaling and iron status in macrophage development, migration, and phagocytosis.
In Aim 2, the PIs propose to undertake complementary approaches to elucidate the regulation of macrophage function by hepcidin-ferroportin-iron signaling in genetically-modified mice with atherosclerosis. Finally, in Aim 3, th PIs will undertake an in vivo screen using transgenic zebrafish to identify novel small molecules that stabilize ferroportin in the presence of hepcidin. Ferroportin-stabilizing compounds will be evaluated for potency, specificity, and conservation of effect in mice. The proposed research program will provide important insights into the roles of hepcidin-ferroportin-iron signaling in macrophage function and inflammatory diseases, as well as new zebrafish and mouse models and small molecule probes. Moreover, the identification of small molecules that stabilize ferroportin may represent novel therapeutic agents for the treatment of inflammatory diseases, including atherosclerotic cardiovascular disease.

Public Health Relevance

Hepcidin regulates iron levels in the blood, in part, by causing macrophages to store iron. However, recent evidence suggests that increased iron levels can activate macrophages, contributing to a variety of diseases associated with inflammation. The proposed research program investigates the regulation of macrophage function by hepcidin-ferroportin signaling and intracellular iron and seeks to discover iron-regulating small molecules that have therapeutic benefits in inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK082971-05A1
Application #
8761113
Study Section
Molecular and Cellular Hematology (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2008-12-01
Project End
2019-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Malhotra, Rajeev; Wunderer, Florian; Barnes, Hanna J et al. (2018) Hepcidin Deficiency Protects Against Atherosclerosis. Arterioscler Thromb Vasc Biol :ATVBAHA118312215
Nigwekar, Sagar U; Bloch, Donald B; Nazarian, Rosalynn M et al. (2017) Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis. J Am Soc Nephrol 28:1717-1722
Vandenwijngaert, Sara; Swinnen, Melissa; Walravens, Ann-Sophie et al. (2017) Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice. Antioxid Redox Signal 26:153-164
Hoeft, Konrad; Bloch, Donald B; Graw, Jan A et al. (2017) Iron Loading Exaggerates the Inflammatory Response to the Toll-like Receptor 4 Ligand Lipopolysaccharide by Altering Mitochondrial Homeostasis. Anesthesiology 127:121-135
Nigwekar, Sagar U; Jiramongkolchai, Pawina; Wunderer, Florian et al. (2017) Increased Bone Morphogenetic Protein Signaling in the Cutaneous Vasculature of Patients with Calciphylaxis. Am J Nephrol 46:429-438
Muenster, Stefan; Lieb, Wolfgang S; Fabry, Gregor et al. (2017) The Ability of Nitric Oxide to Lower Intraocular Pressure Is Dependent on Guanylyl Cyclase. Invest Ophthalmol Vis Sci 58:4826-4835
Zazzeron, Luca; Liu, Chen; Franco, Walfre et al. (2017) Pulmonary Phototherapy to Treat Carbon Monoxide Poisoning in Rats. Shock 47:735-742
Morrell, Nicholas W; Bloch, Donald B; ten Dijke, Peter et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol 13:106-20
O'Rourke, Caitlin; Shelton, Georgia; Hutcheson, Joshua D et al. (2016) Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation. J Vis Exp :
Berra, Lorenzo; Rodriguez-Lopez, Josanna; Rezoagli, Emanuele et al. (2016) Electric Plasma-generated Nitric Oxide: Hemodynamic Effects in Patients with Pulmonary Hypertension. Am J Respir Crit Care Med 194:1168-1170

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