Cell Biology & Biochemistry; Extracellular Matrix; Growth Factors; Proteoglycans; Vascular Biology
Cells within multicellular organisms are in constant communication with one another in order to coordinate tissue, organ and organism-wide responses to changing conditions. Intercellular communication is principally mediated through the extracellular space, and as such, transport and interaction of signaling molecules within the extracellular matrix represents a major point of control in biology. Not surprisingly, disruptions in cell-extracellular matrix communication invariably lead to disease. Our lab has focused on how the composition and mechanical state of the extracellular matrix control protein growth factors. We are particularly interested in how the complex polysaccharide heparan sulfate controls growth factor storage, release and activity within the extracellular space. We study the mechanisms by which structural heterogeneities within heparan sulfate mediate specificity of growth factor binding and activity. We apply a combination of biochemical, molecular, biophysical, and computational approaches in conjunction with cell culture and animal studies to generate a systems biology view of growth factor regulation that incorporates the influence of multiple factors on one another. We apply this approach to studies aimed at understanding the details of growth factor-receptor recognition and activation, the regulation of angiogenesis, and the control of extracellular matrix turnover. The overriding theme to our research is to use quantitative methods to analyze complex biological processes in order to develop predictive models of living systems that can be used to probe basic mechanisms and to assist in the rational design of new therapies for human disease. Currently we are focusing on the involvement of heparan sulfate proteoglycans, vascular endothelial growth factor, fibroblast growth factors, fibronectin, and neutrophil elastase in cardiovascular disease, chronic obstructive pulmonary disease, and retinopathies.
Major Outstanding Questions:
1. What controls the structural complexity of heparan sulfate?
2. How are growth factor specificity and sensitivity modulated by the state of the extracellular matrix?
3. How is extracellular matrix turnover in response to injury controlled in order to maintain structural and functional tissue homeostasis?
4. What catalytic processes modify extracellular matrix structure and function?
Brandeis University, B.A., Ph.D.
Massachusetts Institute of Technology, Postdoctoral Fellowship