Graduate Faculty Directory
William R Law
Department of Biological Sciences
Education
- Post-Doctoral training: Loyola University Medical Center (1986-1988)
- PhD, University of Illinois College of Medicine at Chicago (1985)
- BA, Augustana College (1979)
- BA, Central High for Boys (1974)
Title(s)
Director, Forensic Science Programs
Chair, Biology Department
Faculty Appointments
Professor of Biology
Research Interest
Our laboratory is exploring the role of extracellular purine metabolism in the regulation of purine autocrine and paracrine signaling. Special emphasis is focused on the central position of bound and unbound adenosine deaminase in this process. These studies have far-reaching physiological significance, and are pivotal in the clinical manifestations associated with sepsis and the systemic inflammatory response syndrome (SIRS).
Synopsis
Sepsis and the systemic inflammatory response syndrome are major clinical problems, typically resulting severe infections. The purine nucleoside, adenosine, is recognized as a critical molecule used by cells to modulate a variety of autocrine and paracrine signalling pathways involved in inflammatory processes. Our laboratory research efforts are focused on understanding the role of purine metabolism in modulating inflammatory processes. Currently, we are investigating a dual role for adenosine deaminase (ADA) in the regulation of adenosine signaling. Much of this work is carried out in cell culture using macrophage or fibroblasts cell lines. We have found that ADA serves as a gatekeeper enzyme regulating the deamination of adenosine within the interstitial compartment, and the formation of oxyradical moieties via the xanthine oxidase pathway. In addition, we recently demonstrated that ADA serves as an allosteric regulatory protein, modifying the actions of the adenosine receptors by direct protein-protein interaction on primary macrophages. Confocal microscopy reveals interactions between ADA and the 4 major subtypes of adenosine receptors, A1, A2A, A2B, and A3. Functional response studies reveal that association of ADA with these receptors can increase their sensitivity to adenosine or adenosine receptor agonists. These findings suggest that the coupling of adenosine receptors to ADA favors receptor occupation and activation over enzymatic degradation. Questions as to how ADA is transported out of the cell (it has no signal sequence for secretion or insertion into a membrane), what the structural moieties are that allow ADA to associate with the extracellular domain of adenosine receptors, and the mechanisms underlying regulation of ADA expression by inflammatory processes are being actively pursued. These investigations are likely to lead to new and improved therapeutic management and treatment of sepsis and the systemic inflammatory response syndrome.
Publications & Presentations
LAW, W.R., Conlon, B.A., and Ross, J.D. The Extracellular Cardiac Purine Metabolome in Sepsis. Shock. 28(3):259-264, 2007.
- Ross JD, Ripper R, Law WR, Massad M, Murphy P, Edelman L, Conlon BA, Feinstein DL, Palmer JW, DiGregorio G, Weinberg GL. Adding bupivacaine to high-K cardioplegia improves function and reduces cellular damage of rat isolated hearts after prolonged, cold storage. Anesthesiology, 105(4):746-52, 2006.
- LAW, W.R., Conlon, B.A., and Ross, J.D. The Extracellular Cardiac Purine Metabolome in Sepsis. Shock. (In Press), 2006
- LAW, W.R. Transgenic approaches to reintegration: Adenosine deaminase deficiency improves ischemic tolerance. Cardiovascular Research. 71: 8-9, 2006
- LAW, W.R. Adenosine receptors in the response to sepsis: What do receptor-specific knockouts tell us? American Journal of Physiology: Regulatory, Integrative, and Developmental Physiology. (In Press), 2006
- Conlon BA, Ross JD, LAW WR. Advances in understanding adenosine as a plurisystem modulator in sepsis and the systemic inflammatory response syndrome (SIRS). Frontiers in Bioscience 10:2548-65, 2005
- Law WR, Ross JD, Jonjev ZS. Adenosine attenuates C-terminal but not N-terminal proteolysis of cTnI during cardioplegic arrest. J Surg Res. 123(1):126-33., 2005
- Conlon BA, Law WR. Macrophages are a source of extracellular adenosine deaminase-2 during inflammatory responses. Clin Exp Immunol. 138(1):14-20, 2004
- LAW, W.R., Valli, V.E., and Conlon, B.A. Therapeutic Potential for Transient Inhibition of Adenosine Deaminase in Systemic Inflammatory Response Syndrome. Critical Care Medicine May, 2003.
- Cohen, E.S, LAW, W.R., Easington, C.R., Cruz, K.Q., Nardulli, B.A., Balk, R.A., Parrillo, J.E., and Hollenberg, S.M. Adenosine Deaminase Inhibition Attenuates Microvascular Dysfunction and Improves Survival in Sepsis. Am. J. Resp. Crit. Care Med. (In Press), 2002.
- Adanin, S.,Yalovetskiy, I.V., Narduli, B.A., Sam, A.D., II, Jonjev, Z.S. and LAW, W.R. Inhibiting Adenosine Deaminase Modulates the Systemic Inflammatory Response Syndrome in Endotoxemia and Sepsis, American Journal of Physiology 282: R1324-R1332, 2002.
- Jonjev ZS, Schwertz DW, Beck JM, Ross JD, Law WR. Subcellular distribution of protein kinase C isozymes during cardioplegic arrest. J Thorac Cardiovasc Surg. 126(6):1880-5, 200389:163-168, 2000.
Contact Information
Office:
Science and Technology Center
Room # 342
Box # 38
Phone: 215.596.8919
Fax: 215.596.8710
Email: w.law@usp.edu
