Ali Hafezi-Moghadam, M.D., Ph.D.
Assistant Professor of Ophthalmology
Research
Publications
Projects
Research:
My research focuses on inflammatory aspects of ocular diseases, such as uveitis, diabetic retinopathy (DR) and age-related macular degeneration (AMD). Inflammatory leukocyte accumulation has long been known to damage the host in a variety of diseases. Especially in the eye inflammatory processes can cause significant injury to the retinal neurons and lead to vision loss. Therefore, it is of clinical interest to understand and be able to control inflammation. A number of specialized molecules fulfill distinct functions in the various stages of inflammatory leukocyte recruitment and thus offer attractive targets for treatment of inflammatory diseases. To elucidate the molecular changes to leukocyte surface during disease, we recently developed the autoperfused micro flow chamber assay. In this model a translucent micro flow chamber is placed between the carotid artery and the jugular vein of a live rodent. The animal’s heart continuously perfuses the chamber with blood. Single molecules are immobilized on the chamber surfaces, and leukocyte adhesion to these molecules are studied in live microscopy and under physiologic flow. Using this technique we recently showed for the first time functional integrin upregulation during endotoxin-induced uveitis.
Compared to other organs, ocular tissues enjoy an immune-privileged status, which bars excessive inflammation from the eye. A contributor to the immune-privileged status is the blood-retinal barrier (BRB). Since a compromised BRB is found in many prominent pathologic conditions, my research aims to identify the molecular players involved in the maintenance, regeneration, and decay of this important function. I am particularly interested in understanding the impact of inflammation on the integrity of the BRB. Recently, we introduced a novel link between a molecule secreted by leukocytes and retinal vascular leakage during experimental DR.
Non-invasive detection of molecular events in a living organism can revolutionize medicine. The eye provides a unique portal for visible-light-based imaging of retinal micro-vessels. In a recent work we show, for the first time, non-invasive detection of endothelial injury in the retinal and choroidal vessels of a living animal at an early stage – one that was previously only detectable by most sensitive tests, such as immunohistochemistry or PCR. To achieve this goal we developed unique imaging agents – adhesion-molecule conjugated microspheres – which mimic certain aspects of leukocyte endothelial interaction. Binding of these microspheres to the vascular endothelium provides indication of early disease.
Detection of early endothelial changes during disease would provide physicians with the possibility of earlier therapeutic interventions and, most importantly, prior to the occurrence of irreversible tissue damage. The outreach of the new technology is not limited to the eye. The eye’s vasculature provides a window for imaging, a representative picture of the systemic condition. The retina, being a part of the brain, provides a unique visual access to the barrier-privileged vessels of the central nervous system that might also teach us about the vascular status of the brain. Importantly, conventional techniques of brain and retinal imaging visualize only tissue changes. Our new approach extends our imaging capabilities to the molecular level. Besides being a powerful research tool, this versatile imaging approach holds promise of being useful in the clinical realm and impacting the way we practice medicine.
Representative Publications:
- Hafezi-Moghadam, A., and Ley, K. (1999) Relevance of L-selectin shedding for leukocyte rolling in vivo. J Exp Med 189, 939-948
- Simoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., and Liao, J. K. (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538-541
- Hafezi-Moghadam, A., Thomas, K. L., Prorock, A. J., Huo, Y., and Ley, K. (2001) L-selectin shedding regulates leukocyte recruitment. J Exp Med 193, 863-872
- Hafezi-Moghadam, A., Simoncini, T., Yang, Z., Limbourg, F. P., Plumier, J. C., Rebsamen, M. C., Hsieh, C. M., Chui, D. S., Thomas, K. L., Prorock, A. J., Laubach, V. E., Moskowitz, M. A., French, B. A., Ley, K., and Liao, J. K. (2002) Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8, 473-479
- Hrachovinova, I., Cambien, B., Hafezi-Moghadam, A., Kappelmayer, J., Camphausen, R. T., Widom, A., Xia, L., Kazazian, H. H., Jr., Schaub, R. G., McEver, R. P., and Wagner, D. D. (2003) Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 9, 1020-1025
- Hafezi-Moghadam, A., Thomas, K. L., and Cornelssen, C. (2004) A novel mouse-driven ex vivo flow chamber for the study of leukocyte and platelet function. Am J Physiol Cell Physiol 286, C876-892
- Hafezi-Moghadam, A., Noda, K., Almulki, L., Iliaki, E. F., Poulaki, V., Thomas, K. L., Nakazawa, T., Hisatomi, T., Miller, J. W., and Gragoudas, E. S. (2007) VLA-4 blockade suppresses endotoxin-induced uveitis: in vivo evidence for functional integrin up-regulation. Faseb J 21, 464-474
- Hafezi-Moghadam, A., Thomas, K. L., and Wagner, D. D. (2007) ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage. Am J Physiol Cell Physiol 292, C1256-1262
- Nakao, S., Hata, Y., Miura, M., Noda, K., Kimura, Y. N., Kawahara, S., Kita, T., Hisatomi, T., Nakazawa, T., Jin, Y., Dana, M. R., Kuwano, M., Ono, M., Ishibashi, T., and Hafezi-Moghadam, A. (2007) Dexamethasone inhibits interleukin-1beta-induced corneal neovascularization: role of nuclear factor-kappaB-activated stromal cells in inflammatory angiogenesis. Am J Pathol 171, 1058-1065
- Nakazawa, T., Hisatomi, T., Nakazawa, C., Noda, K., Maruyama, K., She, H., Matsubara, A., Miyahara, S., Nakao, S., Yin, Y., Benowitz, L., Hafezi-Moghadam, A., and Miller, J. W. (2007) Monocyte chemoattractant protein 1 mediates retinal detachment-induced photoreceptor apoptosis. Proc Natl Acad Sci U S A 104, 2425-2430
- Nakazawa, T., Takahashi, H., Nishijima, K., Shimura, M., Fuse, N., Tamai, M., Hafezi-Moghadam, A., and Nishida, K. (2007) Pitavastatin prevents NMDA-induced retinal ganglion cell death by suppressing leukocyte recruitment. J Neurochem 100, 1018-1031
- She, H., Nakazawa, T., Matsubara, A., Hisatomi, T., Young, T. A., Michaud, N., Connolly, E., Hafezi-Moghadam, A., Gragoudas, E. S., and Miller, J. W. (2007) Reduced photoreceptor damage after photodynamic therapy through blockade of nitric oxide synthase in a model of choroidal neovascularization. Invest Ophthalmol Vis Sci 48, 2268-2277
- Hisatomi, T., Nakazawa, T., Noda, K., Almulki, L., Miyahara, S., Nakao, S., Ito, Y., She, H., Kohno, R., Michaud, N., Ishibashi, T., Hafezi-Moghadam, A., Badley, A. D., Kroemer, G., and Miller, J. W. (2008) HIV protease inhibitors provide neuroprotection through inhibition of mitochondrial apoptosis in mice. J Clin Invest
- Miyahara, S., Almulki, L., Noda, K., Nakazawa, T., Hisatomi, T., Nakao, S., Thomas, K. L., Schering, A., Zandi, S., Frimmel, S., Tayyari, F., Garland, R. C., Miller, J. W., Gragoudas, E. S., Masli, S., and Hafezi-Moghadam, A. (2008) In vivo imaging of endothelial injury in choriocapillaris during endotoxin-induced uveitis. Faseb J
- Noda, K., Miyahara, S., Nakazawa, T., Almulki, L., Nakao, S., Hisatomi, T., She, H., Thomas, K. L., Garland, R. C., Miller, J. W., Gragoudas, E. S., Kawai, Y., Mashima, Y., and Hafezi-Moghadam, A. (2008) Inhibition of vascular adhesion protein-1 suppresses endotoxin-induced uveitis. Faseb J 22, 1094-1103
- Skondra, D., Noda, K., Almulki, L., Tayyari, F., Frimmel, S., Nakazawa, T., Kim, I. K., Zandi, S., Thomas, K. L., Miller, J. W., Gragoudas, E. S., and Hafezi-Moghadam, A. (2008) Characterization of azurocidin as a permeability factor in the retina: involvement in VEGF-induced and early diabetic blood-retinal barrier breakdown. Invest Ophthalmol Vis Sci 49, 726-731
- Noda, K., She, H., Nakazawa, T., Hisatomi, T., Nakao, S., Almulki, L., Zandi, S., Miyahara, S., Ito, Y., Thomas, K. L., Garland, R. C., Miller, J. W., Gragoudas, E. S., Mashima, Y., and Hafezi-Moghadam, A. (2008) Vascular adhesion protein-1 blockade suppresses choroidal neovascularization. Faseb J
- Kawahara, S., Hata, Y., Kita, T., Arita, R., Miura, M., Nakao, S., Mochizuki, Y., Enaida, H., Kagimoto, T., Goto, Y., Hafezi-Moghadam, A., and Ishibashi, T. (2008) Potent Inhibition of Cicatricial Contraction in Proliferative Vitreoretinal Diseases by Statins. Diabetes
- Kita, T., Hata, Y., Arita, R., Kawahara, S., Miura, M., Nakao, S., Mochizuki, Y., Enaida, H., Ueno, A., Fujisawa, K., Goto, Y., Shimokawa, H., Hafezi-Moghadam, A., and Tatsuro Ishibashi. (2008) Role of TGF-β in proliferative vitreoretinal diseases and ROCK as a therapeutic target. Proc Natl Acad Sci U S A
- Arita, R., Hata, Y., Nakao, S., Kita, T., Miura, M., Kawahara, S., Zandi, S., Almulki, L., Tayyari, F., Shimokawa, H., Hafezi-Moghadam, A., and Ishibashi, T. (2008) ROCK Inhibition by Fasudil Ameliorates Diabetes-Induced Microvascular Damage. Diabetes
- Almulki, L., Noda, K., Amini, R., Schering, A., Garland, R.C., Nakao, S., Nakazawa, T., Hisatomi, T., Thomas, K.L., Masli, S., and Hafezi-Moghadam, A. (2008) Surprising Upregulation of P-selectin Glycoprotein Ligand-1 (PSGL-1) in Endotoxin-Induced Uveitis. FASEB J
- AMD Role of VAP-1 in choroidal neovascularization
- Diabetic retinopathy Alteration of leukocyte function in diabetes
- Uveitis Finding new targets for uveitis treatment
- BRB Mechanisms of BRB breakdown in health and disease
- Outer BRB Ex vivo examination of rodent RPE explants
- Imaging Non-invasive molecular detection of retinal and choroidal vascular injury
- Inflammation Role of adhesion molecules in major ocular dieseases
