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      Assistant Professor of Medicine

       
      Division of Molecular Medicine
      622 West 168th Street
      New York, NY 10032
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The research in our laboratory centers on several projects directed at understanding the role of matrix metalloproteinases in tissue destruction during certain disease processes.  Our laboratory has made use of transgenic mice in which to express these enzymes at pathophysiological levels in specific tissues so as to recreate the natural proteolytic imbalance that occurs during a disease process.  Through the generation of these transgenic animals we have been able to develop several mouse models of emphysema, atherosclerosis and heart failure and also gain insight into the role these enzymes may be playing in the pathogenesis of these diseases. 

Several years ago we have shown that transgenic mice which express human MMP-1 (matrix metalloproteinase 1, interstitial collagenase) in the lung develop emphysema.  We have recently demonstrated that human patients with emphysema express MMP-1 within their lung parenchyma and normal patients do not.  In this study it was shown that the type II pneumocyte of the lung of patients with emphysema expressed MMP-1 (Imai et al, 2001).  Therefore, we are proceeding with in vitro studies to determine the mechanism by which MMP-1 is induced in the type II pneumocyte.   In our preliminary work we have found that Il-1 and cigarette smoke extract can induce MMP-1 expression in lung epithelial cells.  These studies will allow us to identify the molecular pathway leading to upregulation of MMP-1 in the emphysema lung and possibly provide us with alternative drug targets. 

Changes in the balance of matrix synthesis and degradation are also believed to be important in the process of ventricular remodeling and in the pathophysiology of chronic heart failure. Transgenic mice have been generated harboring a collagenase transgene that dictates cardiac myocyte specific expression (cardiac-collagenase transgenic mice). Histological analyses reveal that the transgenic mouse hearts develop myofibrillar disarray and increased numbers of mitochondria consistent with hypertrophy.  In addition, hemodynamic measurements demonstrated increased left ventricular systolic function in the hearts of these mice at 6 months of age that significantly deteriorates over time when compared to normal mice.  The collagenase transgenic mouse model directly demonstrates a role for MMP-1, in the development of cardiac dysfunction and further implicate this enzyme in the process of cardiac remodeling providing an important new model in which to study these processes.

       NewYork-Presbyterian Hospital

D’Armiento, J., Dalal, S., Okada, Y., Berg, R. A., And Chada, K. (1992).  Collagenase Expression In The Lungs Of Transgenic Mice Causes Pulmonary Emphysema.  Cell, 71:955-961.

Kim, H., Dalal., S.S., Young, E., Legado,M., Weisfeldt, M.L., and D’Armiento, J. (2000)  Disruption of the cardiac matrix leads to altered myocardial function in transgenic mice expressing collagenase (MMP-1) in the heart. J. Clin. Invest. 106:857-866.

Imai, K., Dalal, S., Chen, E.S., Downey , R., Shulman, L., Ginsburg, M., and D’Armiento, J. (2001) Presence of Human Collagenase (MMP-1) in the lung of Patients with Emphysema.  Am. J. Resp, Crit. Care Med. 163:786-791.

Lemaitre, V., O’Byrne, T.K., Borczuk, A. C., Okada, Y., Tall, A.R. and D’Armiento, J (2001) ApoE knock-out mice expressing human interstitial collagenase (MMP-1) in macrophages have less advanced atherosclerosis. J. Clin. Invest. 107:1227-1234.

Foronjy, B. and D’Armiento, J. (2001) The role of collagenase in emphysema.  Respiratory Review. 2:348-352..

D’Armiento, J. (2001) Matrix metalloproteinase Disruption of the Extracellular matrix and Cardiac Dysfunction Trends in Cardiovascular Medicine. In Press.

Lemaitre, V., Soloway, P.D., and D’Armiento, J. (2001) Increased Aortic Aneurysm Formation in ApoE Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1.  Submitted PNAs.

Imai, K., Dalal, S.S., Hambor, J., Okada, Y.,  Horton, W.C., Poole, R.A., and D’Armiento, J. (2001) Bone Growth retardation in Mouse Embryos Expressing Human Collagenase 1. Submitted  J. Cell Biol.

Shiomi, T.,  Okada, Y., Foronjy, B.,  Schiltz, J., Jaenish, R., and D'Armiento, J. (2001). Emphysematous changes are caused by degradation of type III collagen in transgenic mice overexpressing tissue collagenase.  Submitted  Exp. Lung Res.

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Updated: December 20, 2001