M. Amin Arnaout
Chief, Division of Nephrology
Department of Medicine - Gray-Bigelow 1003H
55 Fruit Street
Boston, MA 02114
Lab Members: 5 postdoctoral fellows, 5 junior faculty
Visit my lab page here.
1. Inflammation and repair- Structure and biology of integrins.
2. Genetics of Kidney disease- Autosomal Dominant Polycystic Kidney Disease.
3. Developmental Biology- development of hematopoietic and vascular stem cells.
1. Mounting an inflammatory response to microbial infections depends on the capacity of phagocytic cells to home to the infected organ, traverse the endothelial cell barrier, recognize the microbe and clear it through phagocytosis and cell-mediated killing. Our work traced these vital functions to a family of adhesion receptors called β2 integrins. In phagocytes circulating in the blood, β2 integrins are normally maintained in a low affinity (inactive) state but switch to the high affinity (ligand-competent) state in less than a second in response to agonists, which act intracellularly to release the constrained integrin’s cytoplasmic tails, resulting in a conformational shift of the ectodomain into high affinity. When this tightly regulated process fails, phagocytes become too sticky, leading to subversive inflammation and injury that manifests in ischemia-reperfusion injury syndromes (e.g. heart attack, stroke), nephritis, and autoimmunity. Dysregulated integrin-mediated cell adhesion also contributes to many other diseases including thrombosis and cancer. Ongoing work in our laboratory aims at defining the structural basis of integrin activation and signaling and structure-based drug design, utilizing protein crystallography, cryoelectron microscopy, molecular dynamics, synthetic chemistry, and zebrafish, rodent and primate models of disease.
2. Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disease in humans, and the most common inherited cause of kidney failure in the general population. It is caused by mutations in one of 2 genes, PKD1 and PKD2, and manifests in epithelial- and vascular tube dilations (cysts) leading to kidney failure and life-threatening cerebral hemorrhage, respectively. ADPKD cells display enhanced adhesion and impaired directed migration and defects in planar cell polarity. We have shown that PKD2 encodes PC2, a TRP-like calcium channel, which is regulated by the PKD1 product, PC1. Our current work focuses on elucidating the mechanisms underlying impaired cell-matrix interactions that lead to tube dilation and cyst formation, utilizing biochemical and cell biology approaches in zebrafish and mouse models of ADPKD.
3. Development of blood and blood vessels during embryogenesis is tightly linked, with both systems deriving from a common mesoderm progenitor, the hemangioblast. We have identified a Krüppel-like zinc finger transcription factor as a master regulator of early development of FLK1+ hemangioblasts. Its stable overexpression in murine embryonic stem cells drives hemangioblast development along the hematopoietic lineage to the exclusion of the vascular lineage, and its knockdown in zebrafish or mammalian cells exerts the opposite effects. Ongoing work is aimed at defining the role of this factor in fetal and adult hematopoiesis and angiogenesis, utilizing transgenic and conditional knockout mice, microarrays, stem cell cultures and bone marrow transplantation. Our laboratory is closely integrated into the Harvard Stem Cell Institute and benefits from close collaborations with other Institute members.
Xiong, J.P., Stehle, T., Diefenbach, B., Zhang, R., Dunker, R., Scott, D.L., Joachimiak, A., Goodman, S.L., and Arnaout, M.A. 2001. Crystal structure of the extracellular segment of integrin alphaV beta3. Science. 294:339-45.
Xu,G.M., Sikaneta, T., Sullivan, B.M., Zhang, Q., Andreucci, M., Stehle, T., Drummond, I., and Arnaout, M.A. 2001. Polycystin-1 interacts with intermediate filaments. J Biol Chem. 276: 46544-52.
Xiong, J.P., Stehle, T., Zhang, R., Dunker, R., Joachimiak, A., Frech, M., Goodman, S.L., and Arnaout, M.A. 2002. Crystal Structure of the extracellular domain of integrin alphaV beta3 in complex with an Arg-Gly-Asp ligand. Science. 296:151-5.
Li, X., Xiong, J.W., Shelley, C.S., Park, H., Arnaout, M.A. 2006. The transcription factor ZBP-89 controls generation of the hematopoietic lineage in zebrafish and mouse embryonic stem cells. Development.133:3641-50.
Xiong, J.P., Mahalingham, B., Alonso, J.L., Borrelli, L.A., Rui, X., Anand, S., Hyman, B.T., Rysiok, T., Muller-Pompalla, D., Goodman, S.L., and Arnaout, M.A. 2009. Crystal structure of integrin alphaV beta3 inclusive of a transmembrane fragment defines the beta-genu and orientation of the ectodomain in a lipid bilayer. J. Cell Biol. 1186:589-600.
Mahalingam ,B., Ajroud, K., Alonso, J.L., Anand, S., Adair, B., Horenstein, A.L., Malavasi, F., Xiong, J.P., and Arnaout, M.A. 2011. Stable coordination of the inhibitory Ca2+ ion at the metal-ion-dependent-adhesion site in integrin CD11b/CD18 by antibody-derived ligand aspartate: Implications for integrin regulation and structure-based drug design. J. Immunol. 187: 6393- 6401.
For a complete listing of publications click here.
Last Update: 8/3/2012