Cholesterol Plaques
We intend to develop a procedure in which ultrasound energy acts synergistically with a contrast agent in the vicinity of foam-cell cholesterol domains. Cholesterol crystals develop in atherosclerotic plaques, contributing to plaque instability. Recent studies of the cholesterol crystallization pathway reveal that crystal formation begins in the membrane, where cholesterol aggregates into small (approximately 20 nm in diameter) cholesterol domains.
The source of crystalline cholesterol is human plasma LDL; however, crystals do not nucleate directly from LDL. Rather, crystals arise from macrophage-derived foam cells, where esterified cholesterol contained within the LDL core is converted to free cholesterol. Free cholesterol accumulates within the foam-cell membrane, where it forms cholesterol domains.
This exciting discovery reveals that crystallization may be preventable by dissolving cholesterol domains (in foam-cell membranes) before crystals grow and nucleate. We are investigating the use of contrast-agent-facilitated ultrasound to dissolve cholesterol domains within foam-cell membranes without causing further destabilization.
This project is a collaborative effort with our engineering colleagues:
Molecular Iodine
This work is being conducted in collaboration with Dr. Bernard A. Eskin, Professor in the Department of Obstetrics and Gynecology. Dr. Eskin and colleagues conducted pioneering work investigating iodine activity in the breast. Traditional models of iodine activity in the human body generally assume that iodine behaves in one manner, based on well-documented research with the thyroid. Research completed in the 1970s and 80s by Dr. Eskin and Dr. William R. Ghent revealed that iodine may, in fact, have distinct pathways in breast tissue. Results of this work were the proposed models of iodine activity within breast tissue, describing normal activity, iodine activity in the lactating breast, and a distinct pathway in abnormal breast tissue.
A correlation between iodine and breast cancer was identified over forty years ago. However, clinical application of this knowledge is still in its infancy. Studies demonstrated increased uptake of radioactive iodine in both lactating and neoplastic breast tissue, but not in normal, non-lactating breast tissue. The role of iodine in breast malignancy remains unknown. Most studies focus on the mechanism of iodine uptake in malignant breast tissue; little research considers iodine’s intracellular effects. The overall goal of our research is to clarify effects of intracellular iodine on neoplastic breast processes.
Angiogenesis and Annexin
The role of angiogenesis in malignant tumor growth and development is well known. One of the first documented anti-angiogenesis factors was angiostatin, a potent inhibitor of tumor growth. Treatment with this agent in an animal model of human tumors resulted in complete tumor regression. Clinical trials in humans are underway to evaluate the efficacy of angiostatin.
The cancer community is excited about the potential role of angiostatin and other anti-angiogenesis factors for treatment. However, angiostatin’s mechanism of action and the means by which tumor growth is prevented have yet to be identified. This significantly limits the ability to further exploit angiostatin in the treatment setting. Identification of target(s) and/or receptor(s) is a critical step in further developing the anti-cancer potential of angiostatin.
Current efforts focus on unraveling angiostatin's mechanism of action. Recent work in our lab reveals expression of a protein/receptor on endothelial cells which binds to annexin II. Furthermore, anti-annexin-II antibody mimics angiostatin, inhibiting endothelial cell proliferation and inducing cell death in a dose-dependent fashion. In a murine model, targeted disruption of annexin II by monoclonal antibodies (MAbs) inhibits angiogenesis in vitro and tumor growth.
These findings are encouraging and validate the cancer community’s excitement about the therapeutic potential of anti-angiogenesis agents. Our laboratory is developing these antibodies as a therapeutic molecule for war against cancer. Importantly, this work validates the supposition that anti-angiogenesis therapies can be derived by development of monoclonal antibodies. Additional ongoing research includes identification of cell cycle regulatory proteins in endothelial cells and growth factor regulation of endothelial cells.
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