Biological and Biomedical Science
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M. Amin Arnaout

Chief, Nephrology Division

Department of Medicine - Bigelow 10
Massachusetts General Hospital
55 Fruit Street
Boston, MA 02114
Tel: (617) 726-5663
Fax: (617) 726-5671
Email: arnaout@receptor.mgh.harvard.edu
Web Page: The Arnaout Lab Page
5 postdoctoral fellows, 6 junior faculty

 

Research Interests:

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. Inflammatory diseases of the kidney account for ~ 70% of all cases of kidney failure. Leukocyte infiltration is a major underlying cause in these cases. Our laboratory has identified cell surface receptors named integrins as major players in leukocyte infiltration into organs.  These receptors are normally expressed in a default inactive state, which can readily switch into an active ligand-competent state that can then send mechanochemcial signals to cells to continuously adjust their growth and migratory behavior. Ongoing work in our laboratory aims at defining the structural basis of integrin activation and signaling utilizing protein crystallography, cryoelectron microscopy, in addition to molecular, biophysical and cell biology techniques and animal models. One potential outcome is the discovery of small molecule antagonists to treat inflammatory disease of the kidney and other organs, supplementing and perhaps replacing anti-integrin monoclonal antibodies in current use.

2. Autosomal dominant polycystic kidney disease 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 ciliary genes PKD1 and PKD2 that manifest in a deregulated diameter of tubular structures including kidney tubules and blood vessels, leading to kidney failure and life-threatening cerebral hemorrhage. We have shown that PKD2 encodes a TRP-like calcium channel regulated by the PKD1 product. Our current work focuses on elucidating the factors that regulate expression of PKD1 and PKD2 and the signaling pathways triggered by these TRP-like channels, utilizing biochemical and cell biology approaches in zebrafish and mouse models. 

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, proteomics, stem cell cultures and bone marrow transplantation techniques. These studies may provide novel approaches for expanding bone marrow stem cells for gene transfer, and may prove useful in modulating angiogenesis in health and disease. The laboratory is closely integrated into the Harvard Stem Cell Institute and benefits from close collaborations with other Institute members.

 

References:

  • 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 aVb3. Science. Oct 12;294(5541):339-45.
  • 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 aVb3 in Complex with an Arg-Gly-Asp Ligand. Science. Apr 5;296(5565):151-5, 2002.
  • Adair BD, Xiong JP, Maddock C, Goodman SL, Arnaout MA, Yeager M. 2005. Three-dimensional EM structure of the ectodomain of integrin aVb3 in a complex with fibronectin. J Cell Biol.;168(7):1109-18.
  • 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. Sep;133(18):3641-50.