After completing a B.A. in Human Ecology at the College of the Atlantic in 1997, I received a Ph.D. in Pharmaceutical Sciences from the University of Montana in 2002. I completed a postdoctoral fellowship in the Center for Environmental Health Sciences at the University of Montana. I am currently a Research Assistant Professor in the Department of Biomedical and Pharmaceutical Sciences (2011).
My research focuses on understanding how the environment influences overall health, with an emphasis on the immune system. In my laboratory, ‘environment’ broadly encompasses toxicants, pathogens, natural products, and therapeutic agents. My research seek to define, at the cellular and molecular levels, precisely how environmental exposures modify the function of the innate immune system using a variety of triggers, such as inhaled particulates, models of asthma, natural and synthetic ligands of the AhR, and modulators of system xc-. To conduct my research, we integrate many approaches, including mouse genetics, pharmacological and biochemical modifiers of cellular processes, numerous immunological tools, gene-specific analyses, and state-of-the art multi-color flow cytometry. I strongly believe that a thorough understanding of the cellular and molecular mechanisms that regulate immune response to the environment will lead to the development of improved diagnostic tests, prognostic biomarkers, and therapeutics that can be used to halt or slow disease progression.
Current research projects of in my laboratory include, but are not limited to the following:
(1) Role of the AhR in the development, recruitment, and activation of ILCs.
Collaboration with Drs. David Shepherd (University of Montana) and Thomas Gasiewicz (University of Rochester Medical College).
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that has dual roles as an activator of xenobiotic metabolism and as a regulator of normal homeostasis, organogenesis, and immune activation. While innate lymphoid cells (ILCs) are present the airways, lungs, and draining mediastinal lymph nodes, the study of ILCs is in its infancy--particularly as it relates to their development, regulation, and function in health and disease. Although the AhR has recently emerged as a master regulator for the postnatal maintenance and function of intestinal ILCs, it is not known if the same situation exists in the respiratory tract. The objective of this project is to define how activation of the AhR affects the fate and function of pulmonary ILCs. This data will provide the foundation for manipulation of AhR activation in ILCs as a potential novel therapeutic approach for the treatment of inflammatory lung diseases, as well as a establish a molecular link between environmental exposures and adverse health effects. Demonstrating that the AhR plays a fundamental role in the development, recruitment, and activation of pulmonary ILC3s will be a significant contribution to the field of mucosal immunity.
(2) Aryl hydrocarbon receptor (AhR) mediated regulation of pulmonary innate lymphocytes.
Collaboration with Drs. William Knight and David Shepherd (University of Montana), Dale Umetsu (Harvard), Thomas Gasiewicz (University of Rochester Medical Center), Mike Denison (University of California-Davis) and Dr. Laura Bonati (Università degli Studi di Milano-Bicocca, Italy)
Innate lymphoid cells (ILCs) are a heterogeneous population of cells that function in lymphoid organogenesis, tissue remodeling, antimicrobial and antifungal immunity, and inflammation. Agents that affect the functionality of ILCs are capable of transforming mucosal immunity resulting in either altered susceptibility to disease or therapeutic benefit. Because AhR activation by both endogenous and exogenous AhR ligands is required for IL-22 expression by RORt+ ILCs in vitro and in vivo, and IL-22 has emerged as a prospective mechanism to attenuate pulmonary inflammation, select AhR ligands may represent a means to therapeutically manipulate the function of ILCs and limit pulmonary inflammation. The purpose of this study is to establish that AhR ligands may be useful tools in the treatment of inflammatory lung diseases. We will utilize a select panel of natural and synthetic ligands to: 1) define how AhR activation affects phenotype and function of ILC3s, and 2) determine ligand-binding interactions that correlate with specific physiological outcomes within RORt+ ILC3s. This is particularly innovative because it crosses biomedical disciplines and approaches molecular mechanisms of immune function from a fresh perspective. To our knowledge, no studies have determined the molecular mechanisms underlying the ability of ligands acting via the AhR to differentially modify functionality in RORt+ ILC3s. Moreover, this project is innovative in that the knowledge gained regarding the AhR-ILC-IL-22 signaling axis will provide new targets for the management of respiratory diseases, which would have a significant, positive effect on human health. These studies will also enhance our knowledge of how environmental contaminants adversely affect human health by altering immune function.
(3) Innate lymphoid cells in nanomaterial-induced airway inflammation.
Collaboration with Drs. Gillian Beamer (Cumming School of Veterinary Medicine of Tufts University), Jared Brown (University of Colorado-Denver), and Dale Umetsu (Harvard)
The innate immune system of the lung is one of the most critical physiologic systems for maintaining overall health. Life threatening damage can occur by either failure to rapidly detect and clear inhaled pathogens, or as a result of an unbridled inflammatory response. Although ILCs accumulate in the airways following CNTs exposure and may be an early and critical source of cytokines contributing to the generation of environmentally induced non-allergic asthma (NAA), the cellular and molecular mechanisms underlying these effects remain largely unknown, as does the characteristics of CNTs responsible for initiating these events. These studies are of value because they will define whether ILCs represent a link between toxicants such as CNTs and innate immunity in NAA, and therefore a potential target for therapeutic development. This proposal is also of great importance because it provides the foundation for the development of novel therapeutic strategies aimed at the intentional manipulation of ILCs based upon their capacity to produce and respond to immunoregulatory mediators. In summary, the proposed studies that unravel the regulation and function of ILCs in CNT-induced NAA are not only timely and deserve attention, but also support the causal link between environmental toxicants and chronic inflammatory diseases of the lung. Furthermore, completion of these studies may lead to the discovery of common targets of engineered nanomaterials and new strategies to prevent or ameliorate environmentally mediated diseases.
(4) Understanding the role of the system xc- antiporter in inflammatory bowel disease.
Collaboration with Drs. Sarjubhai Patel and Philippe Diaz (University of Montana), and Gillian Beamer (Cumming School of Veterinary Medicine of Tufts University)
This line of research focuses on a sodium independent amino acid transporter (system xc-), which positively influences antigen presenting cell-mediated T cell activation by providing cysteine to the T cell. Expression of system xc- is elevated on cells of the monocyte/macrophage lineage in the inflamed mucosa of UC and CD patients, as well as in murine models of TNBS induced colitis. Similarly, macrophages and dendritic cells express the high affinity system xc- and its expression levels are highly responsive to stimulation with bacterial toll like receptor ligands in culture, as well as cytokines such as IL-10 and type I interferons. Furthermore, pharmacological inhibitors of system xc- reduced CD69 expression and IFN production by T cells in vitro. Therefore, system xc- may be a novel target for reducing T cell driven inflammation. The goals of this project are to understand the role of system xc- in mucosal immune activation, and evaluate system xc- as a target for more effective treatments against IBD.
(5) Determining the role of scavenger receptors in silico-tuberculosis.
Collaboration with Dr. G.L. Beamer at the Cumming School of Veterinary Medicine of Tufts University.
Silicosis is a progressive, disabling, and often-fatal lung disease resulting from the inhalation of crystalline silica (SiO2) particles over prolonged periods of time. Inhalation of SiO2 particles causes a granulomatous inflammatory response that progresses to interstitial fibrosis, as well as systemic immune deficits. In addition, inhalation of SiO2 predisposes workers to bacterial infections, impairs lung defense mechanisms, and shortens the worker’s lifespan—particularly in less-advanced countries and among disadvantaged persons in developed nations. In particular, SiO2-exposed workers, with or without silicosis, are at increased risk for tuberculosis and non-tuberculous mycobacteria-related diseases. Previous reports suggested that the acute and accelerated forms of silicosis exhibit the highest prevalence of silicotuberculosis, and that the development of mycobacterium tuberculosis (Mtb) infection is directly dependent on the collective SiO2 exposure. Indeed, SiO2 exposure results in a three-fold or greater risk of developing pulmonary Mtb infections. Although the epidemiological relationship between SiO2 exposure and Mtb is well established and mouse models have recently been identified, the cellular and molecular mechanisms underlying increased susceptibility to Mtb infection remain unknown. The current concept is that SiO2 “damages” macrophages or alters their phenotype, thereby inhibiting their ability to phagocytose and kill mycobacteria; however the details behind this change remain unknown.
2014 IL-1R signaling is critical for regulation of multi-walled carbon nanotubes induced acute lung inflammation in C57Bl/6 mice. T.A. Girtsman, C.A. Beamer, N. Wu, M.C. Buford, and A. Holian. Nanotoxicology. Nanotoxicology. Feb; 8(1): 17-27.
2013 Role of the aryl hydrocarbon receptor (AhR) in lung inflammation. C.A. Beamer and D.M. Shepherd. Seminars in Immunopathology. Nov; 35:693–704.
IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. C.A. Beamer, T.A. Girtsman, B.P. Seaver, K.J. Finsaas, C.T. Migliaccio, V.K. Perry, J.B. Rottman, D.E. Smith, and A. Holian. Nanotoxicology. Sep;7:1070-81.
2012 Indole-3-carbinol exerts sex-specific effects in murine colitis. J.A. Benson, C.A. Beamer, B.P. Seaver, and D.M. Shepherd. Eur J Inflamm. Sept-Dec. 10(3):336-346.
Inhibition of TLR ligand- and interferon-g-induced murine microglial activation by Panax notoginseng. C.A. Beamer and D.M. Shepherd. Journal of Neuroimmune Pharmacology. 7(2):465-476.
The Aryl hydrocarbon receptor (AhR) regulates silica-induced inflammation, but not fibrosis. C.A. Beamer, Benjamin P. Seaver, and D.M. Shepherd. Toxicol. Sci. 126(2):554–568.
2010 Innate Immune Processes are Sufficient for Driving Silicosis in Mice. C.A. Beamer, C.T. Migliaccio, F. Jessop, M. Trapkus, D. Yuan, and A. Holian. J Leukoc Biol. 88(3):547-57.
2009 Critical Role of Marco in Crystalline Silica-Induced Pulmonary Inflammation. S.A. Thakur, C.A. Beamer, C.T. Migliaccio, and A. Holian. Toxicol Sci. 108(2):462-71.
2008 Silica suppresses Toll Like Receptor ligand-induced dendritic cell activation. C.A. Beamer and A. Holian. FASEB J. 22(6):2053-63.
2007 Antigen Presenting Cell Population Dynamics During Murine Silicosis. C.A. Beamer and A. Holian. Am J Respir Cell Mol Biol. 37(6):729-38.
2006 Motheaten (me/me) mice deficient in SHP-1 are less susceptible to focal cerebral ischemia. C.A.Beamer, D.M. Brooks, and D.I. Lurie. J Neurosci Res. 83(7):1220-30.
2005 Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure. C.A. Beamer and A. Holian. Am J Physiol Lung Cell Mol Physiol. 289(2):L186-95.
2003 Focal cerebral ischemia upregulates SHP-1 in non-proliferating reactive astrocytes. C.A. Wishcamper, D.M. Brooks, J.D. Coffin, and D.I. Lurie. Brain Res. 974(1-2):88-98.
2001 Lack of the protein tyrosine phosphatase SHP-1 results in decreased numbers of glia within the motheaten (me/me) mouse brain. C.A. Wishcamper, J.D. Coffin, and D.I. Lurie. J Comp Neurol. 441(2):118-33.
2012 C.A. Beamer, B.P. Seaver and D.M. Shepherd. COPD and Other Inflammatory Diseases of the Lung: Focus on AhR signaling. Immunotoxicity, Immune Dysfunction and Chronic Disease. (R Dietert and R Luebke), Humana Press, pp. 313-345.
2010 R.W. Luebke, C.A. Beamer, C. Bowman, J.C. DeWitt, K. Gowdy, V.J. Johnson, D.M. Shepherd, and D.R. Germolec. Immunotoxicology. General & Applied Toxicology, 3rd Edition. (T. Marrs, B. Ballantyne and T. Syversen), John Wiley & Sons, pp. 1561-1583.
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