• Home
  • News
  • Calendar
  • About DF/HCC
  • Membership
  • Visitor Center

Mihaela Gadjeva, PhD

Assistant Professor, Department of Medicine, Harvard Medical School

Assistant Professor, Medicine, Brigham And Women's Hospital

Contact Info

Mihaela Gadjeva
Brigham and Women's Hospital
181 Longwood Ave
Boston, MA, 02115
Phone: 617-525-2268
Fax: 617-525-2510
mgadjeva@rics.bwh.harvard.edu

Assistant

Not Available.

DF/HCC Program Affiliation

Translational Pharmacology and Early Therapeutic Trials

Research Abstract

My research is focused on developing new treatment strategies to regulate inflammatory processes. We have recently established that a protein, named macrophage migration inhibitory factor (MIF), regulates inflammatory responses to bacterial keratitis induced by Pseudomonas aeruginosa. Consistently, we demonstrated that mice deficient for MIF are protected from vision loss as a consequence of an acute P. aeruginosa infection. We demonstrated that MIF regulates cellular adhesion properties, cellular trafficking, and inflammatory responses. Studies are on the way to define the molecular and cellular mechanisms of this protection.

MIF is an integral component of inflammatory responses. The protein is constitutively produced and stored in intracellular pools and, therefore, does not require de novo synthesis before secretion. MIF is rapidly released by a poorly-understood secretory pathway. MIF directly, or indirectly sustains expression of a large panel of pro-inflammatory cytokines such as TNF-a, IFN-g, IL-1b, IL-2, IL-6, IL-8, MIP-2, NO, COX2, products of the arachidonic acid pathway, matrix metalloproteinases. Consistently, our preliminary Affimetrix chip array studies show that out of 14,000 mouse genes tested, 877 are differentially expressed in the P. aeruginosa-infected C57BL6 corneas when compared to the infected MIF KO corneas. Interesting functional categories include adhesion, chemokine receptor binding, chemotaxis, inflammation, defense responses, extracellular matrix, cell communication and cell signaling. The majority of these processes most likely depend on the interaction of MIF with CD74/CD44 receptor complexes, which results in subsequent Mitogen-Activated Protein Kinase (MAPK) activation. Our data agree with the regulatory effects of MIF in mouse models of antigen-induced arthritis, artherosclerosis, Crohn’s disease, endotoxemia and acute pneumonia, where depletion of MIF confers therapeutic benefit. All these characteristics of the MIF molecule suggest that MIF likely has a critical function as an effector molecule early in the course of infection, and a pathologic function when continued production exacerbates inflammation, giving rise to attendant tissue pathology. Consistently, treatment of mice with a small molecular inhibitor of MIF-4-IPP ameliorated disease pathology associated with acute keratitis, suggesting that MIF inhibition is a promising novel therapeutic modality.

Interestingly, MIF is overproduced in B-cell lymphomas, and several types of lung carcinomas, suggesting that MIF pro-migratory and pro-survival functions are key for cancer metastasis. Thus, design of MIF inhibitors is clearly a promising avenue to explore.

Teaching activities:
I actively participate in teaching immunology and microbiology at HMS and FAS, HU.

Publications

View All Publications