Jay K Kolls

UPMC, Pittsburgh, Pennsylvania, United States

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Publications (394)2549.71 Total impact

  • 12/2015; 1(1). DOI:10.1186/s40733-015-0003-5
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    ABSTRACT: Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.
    PLoS ONE 09/2015; 10(9):e0137945. DOI:10.1371/journal.pone.0137945 · 3.23 Impact Factor
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    American Journal of Respiratory and Critical Care Medicine 09/2015; 192(5):634-7. DOI:10.1164/rccm.201501-0047LE · 13.00 Impact Factor
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    ABSTRACT: Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare utilization and cost persist. To address this important clinical condition, the National Heart, Lung, and Blood Institute (NHLBI) convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014 to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop, producing recommendations to guide future research in asthma.
    American Journal of Respiratory and Critical Care Medicine 08/2015; DOI:10.1164/rccm.201505-0963WS · 13.00 Impact Factor
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    ABSTRACT: Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1's endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra(-/-) background. Conversely, IL-17-dependent pathology in Zc3h12a(+/-) mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3' UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ, and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Immunity 08/2015; DOI:10.1016/j.immuni.2015.07.021 · 21.56 Impact Factor
  • American Journal of Respiratory and Critical Care Medicine 08/2015; 192(3):389-391. DOI:10.1164/rccm.201403-0475LE · 13.00 Impact Factor
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    ABSTRACT: Women have an increased prevalence of severe asthma compared with men. IL-17A is associated with severe asthma and requires IL-23 receptor (IL-23R) signaling, which is negatively regulated by let-7f microRNA. We sought to Determine the mechanism by which 17β-estradiol (E2) and progesterone (P4) increase IL-17A production. IL-17A production was determined by using flow cytometry in TH17 cells from women (n = 14) and men (n = 15) with severe asthma. Cytokine levels were measured by using ELISA, and IL-23R and let-7f expression was measured by using quantitative PCR in TH17-differentiated cells from healthy women (n = 13) and men (n = 14). In sham-operated or ovariectomized female mice, 17β-E2, P4, 17β-E2+P4, or vehicle pellets were administered for 3 weeks before ex vivo TH17 cell differentiation. Airway neutrophil infiltration and CXCL1 (KC) expression were also determined in ovalbumin (OVA)-challenged wild-type female recipient mice with an adoptive transfer of OVA-specific TH17 cells from female and male mice. In patients with severe asthma and healthy control subjects, IL-17A production was increased in TH17 cells from women compared with men. IL-23R expression was increased and let-7f expression was decreased in TH17-differentiated cells from women compared with men. In ovariectomized mice IL-17A and IL-23R expression was increased and Let-7f expression was decreased in TH17 cells from mice administered 17β-E2+P4 compared with those administered vehicle. Furthermore, transfer of female OVA-specific TH17 cells increased acute neutrophil infiltration in the lungs of OVA-challenged recipient mice compared with transfer of male OVA-specific TH17 cells. 17β-E2+P4 increased IL-17A production from TH17 cells, providing a potential mechanism for the increased prevalence of severe asthma in women compared with men. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
    The Journal of allergy and clinical immunology 08/2015; DOI:10.1016/j.jaci.2015.05.046 · 11.48 Impact Factor
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    ABSTRACT: Pneumocystis pneumonia remains a common opportunistic infection in the diverse immunosuppressed population. One clear risk factor for susceptibility to Pneumocystis is a declining CD4+ T cell count in the setting of HIV/AIDS or primary immunodeficiency. Non-HIV-infected individuals taking immunosuppressive drug regimens targeting T cell activation are also susceptible. Given the crucial role of CD4+ T cells in host defense against Pneumocystis, we used RNA sequencing of whole lung early in infection in wildtype and CD4-depleted animals as an unbiased approach to examine mechanisms of fungal clearance. In wild-type mice, a strong eosinophil signature was observed at day 14 post Pneumocystis challenge, and eosinophils were increased in the bronchoalveolar lavage fluid of wild-type mice. Furthermore, eosinophilopoiesis-deficient Gata1tm6Sho/J mice were more susceptible to Pneumocystis infection when compared with BALB/c controls, and bone marrow-derived eosinophils had in vitro Pneumocystis killing activity. To drive eosinophilia in vivo, Rag1-/- mice were treated with a plasmid expressing IL-5 (pIL5) or an empty plasmid control via hydrodynamic injection. The pIL5-treated mice had increased serum IL-5 and eosinophilia in the lung, as well as reduced Pneumocystis burden, compared with mice treated with control plasmid. In addition, pIL5 treatment could induce eosinophilia and reduce Pneumocystis burden in CD4-depleted C57BL/6 and BALB/c mice, but not eosinophilopoiesis-deficient Gata1tm6Sho/J mice. Taken together, these results demonstrate that an early role of CD4+ T cells is to recruit eosinophils to the lung and that eosinophils are a novel candidate for future therapeutic development in the treatment of Pneumocystis pneumonia in the immunosuppressed population.
    The Journal of Immunology 07/2015; 195(1):185-193. DOI:10.4049/jimmunol.1403162 · 4.92 Impact Factor
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    ABSTRACT: Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng-/- mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra-/- mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.
    The Journal of clinical investigation 06/2015; 125(8). DOI:10.1172/JCI80911 · 13.22 Impact Factor
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    ABSTRACT: Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with Giardia muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after two weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including β-defensin 1 and resistin-like molecule β. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia. Copyright © 2015. Published by Elsevier Inc.
    Experimental Parasitology 06/2015; 156. DOI:10.1016/j.exppara.2015.06.003 · 1.64 Impact Factor
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    ABSTRACT: Simkania negevensis infection has been hypothesized to play a role in lung transplant rejection. The incidence of S. negevensis infection and its association with acute cellular rejection (ACR) were determined in a prospective cohort study of 78 lung transplant recipients (LTRs) in Toronto, Canada and Pittsburgh, USA from July 2007 to January 2010. S. negevensis testing was detected by quantitative polymerase chain reaction (PCR) on bronchoalveolar lavage fluid. The relationship between S. negevensis and ACR was examined using Cox proportional hazards models and generalized linear and latent mixed models. Cumulative incidence estimates for time-to-ACR in S. negevensis PCR-positive vs. PCR-negative LTRs were 52.7% vs. 31.1% at 6 months and 68.9% vs. 44.6% at 1 year, respectively. Although not statistically significant, there was a trend towards a higher risk of ACR among S. negevensis PCR-positive vs. PCR-negative LTRs in all statistical models. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Clinical Transplantation 05/2015; 29(8). DOI:10.1111/ctr.12571 · 1.52 Impact Factor
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    ABSTRACT: Rationale Stress is associated with asthma morbidity in Puerto Ricans (PRs), who have reduced bronchodilator response (BDR). Objectives To examine whether stress and/or a gene regulating anxiety (ADCYAP1R1) is associated with BDR in PR/non-PR children with asthma. Methods Cross-sectional study of stress and BDR (percent change in FEV1 after BD) in 234 PRs ages 9-14 years with asthma. We assessed child stress using the Checklist of Children's Distress Symptoms (CCDS), and maternal stress using the perceived stress scale (PSS). Replication analyses were conducted in two cohorts. Polymorphisms in ADCYAP1R1 were genotyped in our study and six replication studies. Multivariable models of stress and BDR were adjusted for age, sex, income, environmental tobacco smoke and use of inhaled corticosteroids. Measurements and Main Results High child stress was associated with reduced BDR in three cohorts. PR children who were highly stressed (upper quartile, CCDS) and whose mothers had high stress (upper quartile, PSS) had a BDR that was 10.2% (95% CI= 6.1% to 14.2%) lower than children who had neither high stress nor a highly stressed mother. A polymorphism in ADCYAP1R1 (rs34548976) was associated with reduced BDR. This SNP is associated with reduced expression of the gene for the β2-adrenergic receptor (ADRB2) in CD4+ lymphocytes of subjects with asthma, and affects brain connectivity of the amygdala and the insula (a biomarker of anxiety). Conclusions High child stress and an ADCYAP1R1 SNP are associated with reduced BDR in children with asthma. This is likely due to down-regulation of ADRB2 in highly stressed children.
    American Journal of Respiratory and Critical Care Medicine 04/2015; 192(1). DOI:10.1164/rccm.201501-0037OC · 13.00 Impact Factor
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    ABSTRACT: Acute ethanol intoxication suppresses the host immune responses against Streptococcus pneumoniae. As IL-17 is a critical cytokine in host defense against extracellular pathogens including S. pneumoniae, we hypothesized that ethanol impairs mucosal immunity against this pathogen by disrupting IL-17 production or IL-17R signaling. A chronic ethanol feeding model in SIV-infected Rhesus macaques and acute ethanol in a murine model were used. Transcriptome analysis of bronchial brushes in the non-human primate model showed downregulation of the expression of IL-17 regulated chemokines in ethanol fed animals, a finding also replicated in the murine model. Surprisingly, recombinant CXCL1 and CXCL5 but not IL-17 or IL-23 + IL1β rescued bacterial burden in the ethanol group to control levels. Taken together, this study suggests that ethanol impairs IL-17 mediated chemokine production in the lung. Thus, exogenous luminal restoration of IL-17 related chemokines, CXCL1 and CXCL5, improves host defenses against S. pneumoniae. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and Immunity 03/2015; 83(5). DOI:10.1128/IAI.02869-14 · 3.73 Impact Factor
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    ABSTRACT: Anti-CD20 antibody therapy has been a useful medication to manage non-Hodgkin's lymphoma as well as autoimmune diseases characterized by auto-antibody generation. CD20 is expressed on most developmental stages of B-lymphocytes, thus CD20 depletion leads to B-lymphocyte deficiency. As the drug became more widely used, there was an increase in case reports of patients developing Pneumocystis pneumonia. The role of anti-CD20 and Pneumocystis jirovecii infection is under debate due to the fact that most patients are under a regimen of multiple immunosuppressive medications. To address the specific role of CD20 depletion on host immunity against Pneumocystis, we examined a murine anti-CD20 depleting antibody. We demonstrate that anti-CD20 alone is permissive for Pneumocystis infection and anti-CD20 impaired type 2 immunity, such as IL-4, IL-5, and IL-13, by whole lung cells to Pneumocystis murina. We also demonstrate that CD4+ T-cells from mice treated with anti-CD20 during Pneumocystis infection are incapable of mounting a protective immune response when transferred into Rag1-/- mice. Thus CD20+ cells are critical for generating protective CD4+ T-cell immune responses against this organism. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Infection and Immunity 03/2015; 83(5). DOI:10.1128/IAI.03099-14 · 3.73 Impact Factor
  • Keven M Robinson · Jay K Kolls · John F Alcorn
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    ABSTRACT: Infection with influenza virus has been a significant cause of morbidity and mortality for more than a hundred years. Severe disease and increased mortality often results from bacterial super-infection of patients with influenza virus infection. Preceding influenza infection alters the host's innate and adaptive immune responses, allowing increased susceptibility to secondary bacterial pneumonia. Recent advances in the field have helped to define how influenza alters the immune response to bacteria through the dysregulation of phagocytes, antimicrobial peptides, and lymphocytes. Viral-induced interferons play a key role in altering the phenotype of the immune response. Potential genetic modifiers of disease will help to define additional immunologic mechanisms that predispose to viral, bacterial super-infection with the overarching goal of developing effective therapeutic strategies to prevent and treat disease. Copyright © 2015. Published by Elsevier Ltd.
    Current Opinion in Immunology 02/2015; 34C:59-67. DOI:10.1016/j.coi.2015.02.002 · 7.48 Impact Factor
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    ABSTRACT: Background Influenza is a common respiratory virus and Staphylococcus aureus frequently causes secondary pneumonia during influenza infection, leading to increased morbidity and mortality. Influenza has been found to attenuate subsequent Type 17 immunity, enhancing susceptibility to secondary bacterial infections. IL-27 is known to inhibit Type 17 immunity, suggesting a potential critical role for IL-27 in viral and bacterial co-infection.MethodsA murine model of influenza and Staphylococcus aureus infection was used to mimic human viral, bacterial co-infection. C57BL/6 wild-type, IL-27 receptor ¿ knock-out, and IL-10 knock-out mice were infected with Influenza H1N1 (A/PR/8/34) or vehicle for 6 days followed by challenge with Staphylococcus aureus or vehicle for 24 hours. Lung inflammation, bacterial burden, gene expression, and cytokine production were determined.ResultsIL-27 receptor ¿ knock-out mice challenged with influenza A had increased morbidity compared to controls, but no change in viral burden. IL-27 receptor ¿ knock-out mice infected with influenza displayed significantly decreased IL-10 production compared to wild-type. IL-27 receptor ¿ knock-out mice co-infected with influenza and S. aureus had improved bacterial clearance compared to wild-type controls. Importantly, there were significantly increased Type 17 responses and decreased IL-10 production in IL-27 receptor ¿ knock-out mice. Dual infected IL-10¿/¿ mice had significantly less bacterial burden compared to dual infected WT mice.Conclusions These data reveal that IL-27 regulates enhanced susceptibility to S. aureus pneumonia following influenza infection, potentially through the induction of IL-10 and suppression of IL-17.
    Respiratory Research 02/2015; 16(1):10. DOI:10.1186/s12931-015-0168-8 · 3.09 Impact Factor
  • Florencia McAllister · Jay K. Kolls
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    ABSTRACT: T-helper type 17 cytokines have been implicated in epithelial cancer progression at mucosal sites. In this issue of the European Journal of Immunology, Nardinocchi, et al. [Eur. J. Immunol. 2015. 45: XXXX-XXXX] show that the Th17 cytokines IL-17 and IL-22 can both signal to non-melanoma skin cancer cells, inducing both cellular proliferation and enhanced migration of human basal-cell carcinoma (BCC) and squamous cell carcinoma (SCC) cell lines in vitro. These cytokines were also shown to exacerbate tumor growth in mice injected with the SCC line, CAL27. Thus, IL-17 and IL-22 may be key factors in skin cancer progression and may provide novel prognostic markers in non-melanoma skin cancer.This article is protected by copyright. All rights reserved
    European Journal of Immunology 02/2015; 45(3). DOI:10.1002/eji.201545456 · 4.03 Impact Factor
  • John F Alcorn · Jay K Kolls
    Science 01/2015; 347(6217):26-7. DOI:10.1126/science.aaa4567 · 33.61 Impact Factor
  • Jay K Kolls · Gyongyi Szabo
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    ABSTRACT: Hepatitis C virus (HCV) is a leading cause of chronic liver disease, and efforts to develop therapeutic vaccine strategies have been limited by immune escape due to HCV variants that are resistant to current vaccines or HCV variants that rapidly acquire new resistance-conferring mutations. Recently, the crystal structure of the viral envelope protein E2 region was resolved as well as how E2 docks to the host CD81 protein; therefore, antibodies that block this interaction should prevent viral entry into host cells. In this issue of the JCI, Bailey and colleagues show that immune escape of HCV can occur by naturally occurring polymorphisms in E2 that are distinct from those at mapped sites of antibody binding. These data reveal alternative mechanisms of resistance that need to be considered in both natural viral escape as well as in rationale vaccine design against HCV.
    Journal of Clinical Investigation 12/2014; 125(1):1-2. DOI:10.1172/JCI79424 · 13.22 Impact Factor
  • Jay K Kolls
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    ABSTRACT: The HIV epidemic has clearly demonstrated the critical role CD4(+) T cells play in preventing opportunistic infections in the lung. The types of CD4(+) effector T-cell populations in the lung have significantly expanded over the last 8-10 years with the discovery of helper T type 17 cells, and this review summarizes the field and discusses how these effector cells may be exploited to augment mucosal immunity in the lung.
    12/2014; 11(Supplement 5):S284-S286. DOI:10.1513/AnnalsATS.201403-109AW

Publication Stats

20k Citations
2,549.71 Total Impact Points


  • 2012–2015
    • UPMC
      Pittsburgh, Pennsylvania, United States
    • Stratford University
      Стратфорд, Connecticut, United States
    • University of Lyon
      Lyons, Rhône-Alpes, France
  • 2004–2015
    • University of Pittsburgh
      • • Department of Medicine
      • • Department of Pediatrics
      • • Division of Pediatric Allergy and Immunology
      • • Division of Pediatric Pathology at Children's Hospital of Pittsburgh of UPMC
      Pittsburgh, Pennsylvania, United States
  • 2003–2015
    • Childrens Hospital of Pittsburgh
      • • Department of Pediatrics
      • • Division of Pulmonary Medicine, Allergy and Immunology
      Pittsburgh, Pennsylvania, United States
    • UMC St. Radboud Nijmegen
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 2014
    • Washington University in St. Louis
      • Department of Molecular Microbiology
      San Luis, Missouri, United States
  • 1993–2013
    • Louisiana State University Health Sciences Center New Orleans
      • • Department of Genetics
      • • Section of Pulmonary/Critical Care Medicine
      • • Department of Medicine
      • • Section of Hematology / Oncology
      New Orleans, Louisiana, United States
  • 2009–2012
    • The Children's Hospital of Philadelphia
      • • Division of Neonatology
      • • Department of Pediatrics
      Philadelphia, PA, United States
    • University of Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 2009–2011
    • University of Alabama at Birmingham
      • Department of Pediatrics
      Birmingham, Alabama, United States
  • 2010
    • University of Texas at San Antonio
      • Department of Biology
      San Antonio, TX, United States
  • 2006
    • Thomas Jefferson University
      • Department of Pathology, Anatomy & Cell Biology
      Filadelfia, Pennsylvania, United States
  • 2005
    • The Ohio State University
      • Department of Pediatrics
      Columbus, Ohio, United States
    • Hospital of the University of Pennsylvania
      • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
  • 2002
    • Humboldt-Universität zu Berlin
      Berlín, Berlin, Germany
  • 2001–2002
    • Louisiana State University Health Sciences Center Shreveport
      • School of Medicine
      Shreveport, Louisiana, United States
  • 1995–2002
    • Louisiana State University
      Baton Rouge, Louisiana, United States
  • 1993–1999
    • Tulane University
      New Orleans, Louisiana, United States
  • 1996
    • LSU Medical Center
      New Orleans, Louisiana, United States
  • 1994
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
    • Oakland University
      • Department of Chemistry
      Rochester, Michigan, United States