Careers in Pathology

RESEARCH INTERESTS: Inflammation, innate immunity, inflammatory-mediated diseases, atherosclerosis, Alzheimer's disease, bacterial keratitis, sepsis, antibiotic peptides, leukocyte biology, and leukocyte-endothelial interactions.

This laboratory investigates the role of a novel inflammatory mediator known as CAP37. For the past 15 years we have been exploring the significance of this protein in host defense against severe infection and in various inflammatory mediated diseases. We currently employ a combination of cellular, immunological, biochemical and molecular approaches at the in vitro and in vivo level to solve these questions. Our long-term goals are to design new and effective antibiotics and anti-inflammatory therapeutics.

CAP37 is a natural antibiotic that is localized to the granules of human neutrophils and serves to protect the host from infection. It is particularly active against Gram negative bacteria such as Salmonella typhimurium and Escherichia coli. We have synthesized a peptide based on the native CAP37 sequence that mimics the antimicrobial action of the protein. The efficacy of these peptides has been tested in animal models and we have successfully demonstrated that they can rescue mice and rats from lethal infections. We are currently investigating the mechanism by which CAP37 protects the host from severe infections.

In addition to its effect on bacterial cells, CAP37 has a wide repertoire of functions on mammalian cells. The central focus in these studies is our research on the immunomodulatory effect of CAP37 on cells of the mononuclear phagocyte system such as monocytes in the systemic circulation and microglia in the central nervous system, and on endothelial cells in the vasculature. We hypothesize that CAP37 plays a pivotal role in the emigration of mononuclear cells across the endothelium into the extravasculature due to its potent chemotactic activity, and its ability to up regulate adhesion molecules on the surface of monocytes and endothelium. Projects include the delineation of bioactive peptides based on the amino acid sequence of native CAP37 in the hope of discovering small peptides that would serve as anti-inflammatory agents. Another important aspect of our research is the identification and cloning of the CAP37 receptor on monocytes and endothelial cells. These studies would lead to the identification of the important signal transduction pathways utilized by CAP37 in effecting these various functions. We have recently demonstrated the presence of CAP37 in atherosclerotic plaques and are exploring the role this protein might play in the initiation and or exacerbation of this disease by studying its effect on the activation of monocytes, endothelium, and smooth muscle cells.

In addition to its role as an inflammatory mediator in the systemic system, we have recent evidence that CAP37 may play a role in central nervous system inflammation. This is based on our findings that CAP37 is present in brains of patients dying from Alzheimer’s disease and that it is a potent regulator and activator of microglial cell function. It has been postulated that inflammation in the central nervous system may play a role in the pathogenesis of Alzheimer’s disease. We hypothesize that CAP37 may recruit and activate microglia thus contributing to the initiation and/or augmentation of Alzheimer’s disease. Projects are designed to determine the mechanism of activation of microglia by CAP37 and whether it might contribute to the death of neurons.

In our most recent findings we have used a rabbit model of bacterial keratitis to further investigate the biological significance of CAP37 in infections and inflammation in the eye. Bacterial keratitis is a common clinical problem and is often seen in those who have sustained penetrating corneal injuries, have used extended wear contact lenses, have undergone incisional refractive surgery or are immunocompromised. Our studies are designed to investigate the role of CAP37 in corneal wound healing following infections of the eye.