The candidate received extensive training in the physical sciences early in her scientific career and has several years of experience studying quantitative problems in physics and biophysics. She applied polymer physics and polyelectrolite theory to characterize DNA double helix electrostatic interactions, and low-temperature magnetic circular dichroism spectroscopy to study the active site of heme proteins. As a contractor to the intramural NIH, she investigated resolution and band spreading in gel electrophoresis. Additional studies were aimed at the improvement of existing and the development of new electrophoretic techniques. Most recently, she began to shift my research interest to biological problems. Specifically, for the past four years she has studied actin and actin binding proteins, primarily by applying the quantitative techniques that characterized her earlier research. I found that I can apply my quantitative skills, both theoretical and experimental, very effectively in this area. Also, I found the biological nature of this work to be very interesting and exciting. Working with Dr. Michael Bubb (my mentor for the current proposal), we have developed new insights into the mechanism by which actin-binding proteins regulate actin filament dynamics. For example, our studies have identified a ternary complex of profilin, actin, and thymosin beta4, and in our recent paper, we reveal the potential significance of this finding. Thymosin beta4 is an intriguing protein, which is a prevalent component of developing and regenerating muscle, where it functions to regulate actin filament organization and control cytoskeletal dynamics. Recently it was discovered that thymosin beta4 is post-translationally modified and secreted as thymosin beta4 sulfoxide when macrophages are treated in situ with glucocorticoids. Moreover, thymosin beta4 sulfoxide has been shown to have both anti-inflammatory and immunosuppressive properties. This indicates that therapies that regulate production and/or secretion of thymosin beta4 could have great potential advantages over steroidal drugs used as anti-inflammatory therapy, because thymosin beta4 sulfoxide would be expected to reproduce the benefits of glucocorticoids without their toxicity. My short-term career objective is to develop understanding and proficiency in immunology and cell biology. My long-term research objective is to exploit the anti-inflammatory and immunosuppressive effects of thymosin beta4 for the treatment of autoimmune disease, with the more general objective being the application of my quantitative skills to biology and medicine. As an initial step toward these goals, I specifically propose to investigate the mechanism by which thymosin beta4 is oxidized, secreted, and recognized by cells of the immune system.
