Rick A. Wetsel, Ph.D.
The William S. Kilroy, Sr. Chair in Pulmonary Disease
Professor;
Center for Immunology & Autoimmune Diseases
Director, Laboratory for Developmental Biology
phone 713.500.2412;
fax 713.500.2420
Rick.A.Wetsel@uth.tmc.edu
Dr. Wetsel's research interests are directed at understanding the molecular events involved in mediating the inflammatory and immune response in both normal and pathological conditions. His laboratory is also interested in the development of novel therapeutics via embryonic stem cell research.
Dr. Wetsel graduated in 1976 from the University of Texas in Austin with a Bachelor of Science degree in Chemistry. In 1982, he received his Ph.D. in Biochemistry from the University of Texas Health Science Center in San Antonio.
His postdoctoral training was performed from 1983 through 1986 at the Scripps Research Institute, Department of Molecular Immunology, La Jolla, CA. In 1986, he was appointed as Assistant Professor of Pediatrics and Molecular Microbiology at Washington University School of Medicine in St. Louis, MO.
In 1992, he was a visiting scientist at the Basel Institute for Immunology, Basel, Switzerland. In 1996, he joined the faculty at UT-Houston, Institute of Molecular Medicine for the Prevention of Human Diseases, where he is a Professor of Molecular Medicine in the Research Center for Immunology and Autoimmune Diseases. He is also the Director of the Laboratory for Developmental Biology in the Institute, which oversees the production of transgenic and "knock-out" animal models.
Dr. Wetsel has received the Mead Johnson Excellence of Research Award and the James W. McLaughlin Award in Infectious Disease and Immunology, as well as a NIH Research Career Development Award to support his work from 1989 through 1994. He was Associate Editor for the Journal of Immunology from 1995 through 2000 and has served on several NIH study sections and other national and international foundation peer review committees, including the Arthritis Foundation (Inflammation), which he chaired from (2004 to 2006). He is currently the chair of the NIH Innate Immunity and Inflammation Study Section (III). Dr. Wetsel is a member of the American Society for Biochemistry and Molecular Biology, American Association of Immunologists, American Association for the Advancement of Science, American Chemical Society, American Society for Microbiology, and the International Complement Society (ICS). He has served on the board of the ICS as Treasurer since 2005.
Dr. Wetsel's research interests are directed at understanding the molecular events involved in mediating the inflammatory and immune response in both normal and pathological conditions. Initial studies were focused on delineating the molecular genetic mutations that caused inherited deficiencies and biological defects of the innate immune system. More recently, these research efforts have been focused on studies of the complement anaphylatoxin receptors. These receptors are seven-transmembrane G-protein coupled receptors that mediate numerous biological events in inflammation and immunity, including smooth muscle contraction, histamine release from mast cells, vasodilation and directed migration of numerous peripheral blood leukocytes. These receptors have also been implicated in playing major roles in numerous diseases, including rheumatoid arthritis, asthma, psoriasis, lupus and atherosclerosis.
To examine the requisite role of the anaphylatoxin receptors in these and other diseases, Dr. Wetsel's laboratory has generated several "knock-out" mice in which the genes encoding these receptors and their ligands have been selectively inactivated by gene targeting and homologous recombination methods. These mice have been employed in studies of a mouse model of asthma, which revealed that the C3a complement anaphylatoxin peptide is a major contributor to the Th2 effector functions observed in asthma.
The overall goal of his research program for the next several years is to increase the understanding of specific and overall roles that complement anaphylatoxin peptides and their receptors play in inflammation and immunity. These studies will be driven by the central hypothesis that the complement anaphylatoxin receptors are expressed by numerous different cell types, including tissue parenchymal cells of nonmyeloid origin, and that these receptors mediate numerous biological activities that are critical for the initiation and perpetuation of important proinflammatory pathways required for a robust immune system. In addition, research will be performed to delineate and evaluate the overall biological significance of the carboxypeptidases CPN, CPR, and CPM in regulating inflammatory, innate, and adaptive immune responses mediated by the complement anaphylatoxins. These later studies will be carried out using specific carboxypeptidase "knock-out" mice that have been generated recently in the Wetsel laboratory.
Specifically, investigations are planned to 1) determine the biological functions and in vivo significance of the complement anaphylatoxins (C3a and C5a) and their regulatory plasma carboxypeptidases in coagulation and fibrinolysis, 2) to determine the biological functions of the complement anaphylatoxins (C3a and C5a) and their regulatory carboxypeptidases in mediating inflammation, cellular recruitment, and hypotension in vivo, and 3) to delineate the cellular and molecular mechanisms by which the complement anaphylatoxins, their receptors, and the carboxypeptidases modulate immunity and inflammation in response to bacterial infections. Collectively all these studies will help evaluate the complement anaphylatoxins, their receptors, and their regulatory carboxypeptidases as possible therapeutic targets for drug intervention in inflammatory and allergic disorders.
A new area of focus in the Wetsel laboratory is the therapeutic use of embryonic stem cells in the replacement and/or regeneration of damaged tissue. This work is currently supported by the Clive and Nancy Runnells Program for Embryonic Stem Cell Research at the University of Texas-Houston. The overall goals of this research program are: 1) to develop culture and genetic selection procedures that will facilitate the differentiation of embryonic stem (ES) cells into pure populations of transplantable tissue cells, and 2) to generate a universal donor embryonic stem cell line that can be differentiated and transplanted without undergoing graft rejection by the patient’s immune system. These research efforts have led to the generation of the first pure population of lung alveolar epithelial type II cells from human ES cells. These cells hold promise as a practical transplantable source of pulmonary epithelial cells that could be used in the future to repair damaged lung alveolus due to chronic pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD) and in therapeutic treatment of genetic diseases affecting the lung, such as surfactant protein deficiencies.
Recent Publications (Selected From 89 Total)
Wang D, Haviland DL, Burns AR, Zsigmond E, Wetsel RA. A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc Natl Acad Sci. 2007, 104: 4449-4454.
Nelson KC, Zhao M, Schroeder PR, Li N, Wetsel RA, Diaz LA, Liu Z. Role of different pathways of the complement cascades in experimental bullous pemphigoid. J Clin Invest. 2006; 116: 2892-2900.
Huber-Lang M, Sarma JV, Zetoune FS, Rittirsch D, Neff TA, McGuire SR, Lambris JD, Warner RL, Flierl MA, Hoesel LM, Gebhard F, Younger JG, Drouin SM, Wetsel RA, Ward PA. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006; 12: 682-687.
Mueller-Ortiz SL, Hollmann TJ, Haviland DL, Wetsel RA. Ablation of the Complement C3a Anaphylatoxin Receptor Causes Enhanced Killing of Pseudomonas aeruginosa in a Mouse Model of Pneumonia. Am J Physiol Lung Cell Mol Physiol. 2006; 291: 157-165.
Drouin SM, Sinha M, Sfyroera G, Lambris JD, Wetsel RA. A Protective Role for the Fifth Complement Component (C5) in Allergic Airway Disease. Am J Respir Crit Care Med. 2006; 173: 852-857.
Mueller-Ortiz S, Drouin SM, Wetsel RA. The alternative activation pathway and complement component C3 are critical for a protective immune response against Pseudomonas aeruginosa in a murine model of pneumonia. Infect Immun 2004, 72:2899-2906.
Matthews, KW, Mueller-Ortiz, SL, Wetsel RA. Carboxypeptidase N: A pleiotropic regulator of inflammation. Molec Immunol 2004, 40:785-793.
Girardi G, Berman J, Redecha P, Spruce L, Thurman JM, Kraus D, Hollmann TJ, Casali P, Carroll MC, Wetsel RA, Lambris JD, Holers VM, Salmon JE. Complement C5a receptors and neutrophils mediate fetal injury in the antiphospholipid syndrome. J Clin Invest 2003; 112:1644-1654.
Drouin SM, Corry DB, Hollmann TJ, Kildsgaard J, Wetsel RA. Absence of the complement C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J Immunol 2002, 169:5926-5933.
Drouin SM, Corry DB, Kildsgaard J, Wetsel RA. Cutting Edge: The absence of C3 demonstrates a role for complement in Th2 effector functions in a murine model of pulmonary allergy. J Immunol 2001; 167:4141-4146.
Drouin SM, Kildsgaard J, Haviland J, Zabner J, Jia HP, McCray PB, Tack BF, Wetsel RA: Expression of the complement anaphylatoxin C3a and C5a receptors on bronchial epithelial and smooth muscle cells in models of sepsis and asthma. J Immunol 2001; 166:2025-2032.
Kildsgaard J, Hollmann TJ, Matthews KW, Bian K, Murad F, Wetsel RA: Cutting Edge: Targeted disruption of the C3a receptor gene demonstrates a novel protective anti-inflammatory role for C3a in endotoxin-shock. J Immunol 2000; 165:5406-5409.
Wetsel RA, Kulics J, Lokki M‑J, Kiepiela P, Akama H, Johnson CAC, Densen P, Colten HR: Type II human complement C2 deficiency: Allele‑specific amino acid substitutions (Ser189 to Phe; Gly444 to Arg) cause impaired C2 secretion. J. Biol. Chem. 1996; 271:5824‑5831.
Wang X, Fleischer DT, Whitehead WT, Haviland DL, Rosenfeld SI, Leddy JP, Snyderman R, Wetsel RA: Inherited human complement C5 deficiency: Nonsense mutations in exons 1 (Gln1 to Stop) and 36 (Arg1458 to Stop) and compound heterozygosity in three African‑American families. J. Immunol. 1995; 154: 5464‑5471.
Haviland DL, McCoy RL, Whitehead WT, Akama H, Molmenti EP, Brown A, Parks WC, Perlmutter DH, Wetsel RA: Cellular expression of the C5a anaphylatoxin receptor (C5aR): Demonstration of C5aR on non‑myeloid cells of the liver and lung. J. Immunol. 1995; 154:1861‑1869.
Wetsel RA: Structure, function and cellular expression of the complement anaphylatoxin receptors. Curr. Opin. Immunol. 1995; 7:48-53.