Measurement and Modeling of Inflammation

Measurement and Modeling of Inflammation
Graduate Student Researcher: Samuel Shimp

We are making significant advances in defining mechanisms of cell signaling networks associated with inflammation through extensive in vitro laboratory work as well as in vivo mouse studies. Our mechanistic, computational models are enhancing our understanding of autoimmune pathogenesis and cancer thermal therapies, leading to the design of novel therapeutic strategies. Some of our most significant results show modulation of the immune response through control of heat shock protein chaperone activity.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder that can affect nearly every organ in the body. One of our areas of expertise in the heat transfer and nanotherapeutics lab is that of imaging and measuring heat shock protein activity. Heat Shock Protein 90 (Hsp90) is known to chaperone numerous signaling client proteins including those involved with inflammation and anti-apoptotic pathways. I am exploring the link between Hsp90 and chronic autoimmune disease pathogenesis through the use of Hsp90 inhibitors to regulate Hsp90 activity. One inhibitor employed is an anti-cancer drug in phase 3 clinical trials known as Alvespimycin (17-DMAG). 17-DMAG inhibits Hsp90 function by binding to the carboxyl (C-) terminal domain resulting in deactivation, destabilization, and degradation of Hsp90 inflammatory signaling clients, such as Akt, for decreased inflammation. Our long-term goal is to elucidate and mathematically model the cellular mechanisms of the Hsp90 modulated inflammatory pathways in autoimmune diseases such as SLE.

My research uses J774 mouse macrophage cells and mouse kidney (mesangial) cells for in vitro studies. I also perform studies using New Zealand Black x White (NZB/W) and MRL/lpr mouse models of lupus nephritis for in vivo studies.

Relevant Publications & Conferences:
C. Chafin, S. Muse, R. Hontecillas, J. Bassaganya-Riera, D. Caudell, S. Shimp, M. N. Rylander, J. Zhang, L. Li, and C. Reilly, 2010, "Deletion of PPAR-gamma in Immune Cells Enhances Susceptibility to Anti-GBM disease," Journal of Inflammation Research, 3: 127-134.
Shimp III, S. K., Reilly, C. M., Rylander, M. N., "Computational Modeling of Hsp90 inhibition illustrates a potential therapy to inhibit immune mediated inflammation in systemic lupus erythematosus", American Association of Immunologists, Annual Meeting May 7-12, 2010, Baltimore, MD.
Shimp, S. K., Reilly, C. M., Rylander, M. N., "Computational modeling of Hsp90 as a therapeutic target to inhibit immune-mediated inflammation in systemic lupus erythematosus", College of William & Mary 9th Annual Graduate Research Symposium, March 26-27, 2010, College of William & Mary, Williamsburg, VA.
A. Peairs, R. Dai, L. Gan, S. Shimp*, M. N. Rylander, L. Li, C.M. Reilly. 2010, "Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells," Cellular Molecular Immunolology, 7(2):123-32.
Shimp, S. K., Peairs, A., Reilly, C. M., Li, L., Rylander, M. N., 2008, "Cytokines and hepatoneogenesis through an indirect mechanism involving heat shock protein 90", Poster Presentation at 6th Annual Via Research Recognition Day 16 Oct. 2008, Virginia College of Osteopathic Medicine, Blacksburg, VA.
Bradley, A. T., Evans, W. C., Reed, J. L., Shimp, S. K., Fitzpatrick, F. D., 2008, "TEM Cell Testing of Cable Noise Reduction Techniques from 2 MHz to 200 MHz – Part 1" - Asia-Pacific EMC Week And Technical Exhibition Singapore, May 19-23, 2008
Bradley, A. T., Evans, W. C., Reed, J. L., Shimp, S. K., Fitzpatrick, F. D., 2008, "TEM Cell Testing of Cable Noise Reduction Techniques from 2 MHz to 200 MHz – Part 2" - Asia-Pacific EMC Week And Technical Exhibition Singapore, May 19-23, 2008
Shimp, S. K., Southward, S. C., Ahmadian, M., 2007, "Detecting Crew Alertness With Processed Speech" ASME/IEEE Joint Rail Conference and Internal Combustion Engine Spring Technical Conference, March 13-16, 2007, Pueblo, CO, USA

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