Margaret A Schwarz, MD CAB 7036 732-235-7155 schwarm2@umdnj.edu

Our two main areas of interest are the vascular contributions to lung and tumor development. The lung developmental studies examine the molecular interactions between fetal lung neovascularization and lung epithelial morphogenesis. Although partitioning lung morphogenesis and neovascularization into individual processes is attractive, it is becoming more apparent that it is the interaction of these two components that contribute to normal lung formation. What is less clear, is the dependence of these two processes on each other. Neovascularization has been shown to be a key regulatory process in fetal growth and development. Alterations within this process can lead to concomitant vascular and tissue abnormalities identified within lung dysplasia. Although a significant amount of information exist regarding the pathologic progression of dysplastic lung diseases, little is known regarding the molecular mechanisms that regulate their formation. The goal of our research is to establish whether the vasculature is a determinant of normal distal lung morphogenesis. We have developed in vitro and in vivo strategies to identify the fundamental components of distal lung morphogenesis regulated by neovascularization, but may also be potential regulators of angiogenesis .

Neovascularization is critical to tumor formation. Discovering those mechanisms that inhibit intra-tumor vessel formation is one of the essential pieces needed to improve cancer treatment. Although a significant amount of information exist regarding negative regulators of the tumor vessel formation, less is known regarding the molecular mechanisms that activate these anti-angiogenic compounds. The goal of our research is to determine those mechanisms that drive activation of these negative growth factors. To this end we are examining one such compound in great detail. Endothelial-Monocyte Activating Polypeptide (EMAP) II is a unique, leaderless, single chain polypeptide protein first identified from murine fibrosarcoma. In its precursor (p) form, it is 34-kDa molecule and is processed by unknown mechanisms to a mature 21-kDa form. Mature EMAP II (mEMAP II) is an extracellular molecule that is known to activate endothelial cells, neutrophils and mononuclear phagocytes and appears to be a proinflammatory mediator with the capacity to prime tumor vasculature for a locally destructive process or be anti-angiogenic in its own capacity. Thus, identifying factors that govern the intracellular processing of pEMAP II and ultimately affect its secretion are critical determinants of the biological role of EMAP II and will provide insight into the determinants by which a balance of pEMAP II / mEMAP II can affect tumor development.

Figures relating to the above experiment (PDF 6.0)

1. Schwarz MA, Kandel, J., Brett, G., Li, J., Hayward, J., Schwarz, RE, Chappey, O., Wautier, J., Chabot, J., Lo Gerfo, P., and Stern, D.; Endothelial-Monocyte Activating Polypeptide (EMAP) II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth, and induces apoptosis in growing endothelial cells. J. Exp. Med., 190(3):341-354, 1999.
2. Schwarz, M., M. Lee, J. Zhao, F. Zhang, Y. Jin, S. Smith, J. Bhuva, D. Stern, D. Warburton, and V. Starnes EMAP II: A Modulator of Neovascularization in the Developing Lung. Am. J. Physiol., 276 (Lung Cell. Mol. Physiol.) 20:L365-375, 1999.
3. Schwarz, MA, Zhang, F., Lane, J., Schachtner, S., Jin, Y., Deutsch, G., Starnes, V. and Pitt, BR, Angiogenesis and Morphogenesis of Murine Fetal Distal Lung in an Allograft Model. Am J Physiol Lung Cell Mol Physiol 278: L1000-L1007, 2000
4. Schwarz, MA, Zhang, F., Gebb, S., Starnes, V. and Warburton, D. EMAP II Inhibits Lung Neovascularization and airway epithelial morphogenesis. Mech Dev., 95:123-132, 2000 .
5. Zheng, M, Schwarz, MA, Lee, S., Kumaraguru, U., and Rouse, BT Control of stromal keratitis by inhibition of neovascularization. Am. J. Patholo. 159(3):1021-1029, 2001.
6. Zhang, FR and Schwarz, MA Pro - Endothelial-Monocyte Activating Polypeptide (EMAP) II is not primarily cleaved by caspase 3 and 7. Am J Physiol Lung Cell Mol Physiol 282:L1239-44, 2002.
7. Quintos, ML., White, CW. and Schwarz, MA Potential role for anti-angiogenic proteins in the evolution of Bronchopulmonary Dysplasia. Antioxid Redox Signal. Feb; 6(1): 137-45, 2004.
8. Schwarz, MA, Wan, ZS, Lui, J. and Lee, MK Epithelial-mesenchymal interactions are linked to neovascularization. Am J Respir Cell Mol Biol. Jun;30(6):784-92.2004
9. Schwarz, RE, and Schwarz, MA In vivo therapy of local tumor progression by targeting vascular endothelium with EMAP II. J Surg Res. Jul 1;120(1):64-72, 2004.
10. Thompson, JL, Ryan, JA, Barr, M., Franc, B., Starnes, V., and Schwarz, MA. A role for anti-angiogenic proteins in the repair process following myocardial infarction. J Surg Res 116(1):156-164, 2004.