Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.
Katie Alexander, PhD H. pylori infection is firmly established as a risk factor for the development of gastric adenocarcinoma, but relatively little is known about how its colonization of the stomach contributes to epithelial dysfunction, particularly at the stem cell level. My current research project uses stem cell organogenesis to examine H. pylori infection in the human stomach and determine whether infection upregulates epithelial ST6Gal-I expression, a glycosyltransferase that is overexpressed in multiple mucosal cancers including ovarian, pancreatic and colonic. In another project, I have uncovered a dysregulation of ST6Gal-I expression in Barrett’s esophagus, a pre-cancerous lesion that is associated with an increased risk of developing esophageal adenocarcinoma. Furthermore, I also am interested in the epigenetic regulation of mucosal cancers.
Noel K. Childers, DDS, PhD Dr. Childer's current studies involve investigations aimed at identifying safe and effective mucosal immunization delivery systems. Specifically, studies examine the characteristics of liposomes that are important in potentiating immune responses to orally or nasally administered S. mutans antigens. This involves in vitro studies of the physical characteristics of liposomal antigen preparations as well as in vivo studies into the uptake and processing of liposome preparations in rats. Following animals studies of the efficacy of liposomal S. mutans antigen vaccines, studies have been initiated for human FDA Phase I clinical trials studying the safety and immunogenicity of liposomal oral and nasal immunization. The overall goal of these studies are to identify a safe and effective oral immunization strategy which is protective against dental caries.
Clinical research interests also include studies to determine risk factors for oral complications in children with cancer and HIV infection. These studies have assessed various clinical and immunological factors involved in the development of oral lesions in medically compromised children. The goal of this research is to develop and test protocols that will prevent the occurrence or severity of oral complications in children identified to be at risk. Additionally, research efforts have involved assessment of the prevalence of dental disease in children as related to access to care. Related studies have assessed the effectiveness of dental sealants in prevention of dental caries using Medicaid claims as well as Jefferson County Department of Public Health records.
James F. Collawn, PhD Dr. Collawn's laboratory studies receptor-mediated endocytosis (RME) and protein trafficking. The first area of focus is to examine the polarized trafficking of two integral membrane proteins in epithelial cells, the transferrin receptor (TR) and the cystic fibrosis transmembrane conductance regulator (CFTR). TR is expressed in nearly all mammalian cells and its itinerary is well characterized by us and others. CFTR is a cAMP activated chloride channel and its transit through the secretory and endocytic pathways is just beginning to be understood. Cystic fibrosis (CF), the most common genetic disorder in the Caucasian population, results from defective processing or function of the CFTR protein. Therapeutic approaches have focused on increasing the amount or improving the function of defective CFTR at the apical membrane. However, until the exact physiological functions and trafficking pathways of wild-type CFTR have been characterized, such treatments remain only empirical. Using biochemical and physiological approaches, Dr. Collawn's group is studying the cellular mechanisms that regulate wild-type CFTR biogenesis, endocytosis, recycling and function. They are also comparing the above features of the wild type protein to naturally-occurring CFTR mutants in order to understand the metabolic and functional defects in these proteins that result in a certain disease phenotype. The group's second area of research is to develop methods that will establish safe and effective strategies for immunization or for induction of immunologic tolerance. Using phage display analysis, Dr. Collawn's lab has identified peptides that bind to cell surface receptors on dendritic and B cells. They are screening for specific receptors that undergo RME in order to develop methodologies for enhancing antigen uptake and processing by antigen-presenting cells in vitro. Using a well-defined transgenic animal model, they are testing the effectiveness of different peptide sequences identified by phage display to promote antigen uptake and presentation and are using this methodology to study how this might be used to either enhance or suppress helper T cell responses in vivo. These studies employ both cell biological and immunological techniques to understand how helper T cell responses are regulated in vitro and in vivo.
Jessy Deshane, PhD Dr. Deshane is committed to an academic career combining basic and translational research with an emphasis on inflammatory diseases of the airway. The focus of Dr. Deshane's research program is to enhance our understanding of the role of myeloid-derived regulatory cells in chronic airway inflammatory diseases. Asthma is a chronic inflammatory disease of the airways in which innate and adaptive immune cells participate as drivers of the inflammatory response. Free radical species have long been implicated as critical mediators of the asthmatic inflammatory process. Dr. Deshane's studies in a mouse model of allergic airway inflammation have established that subsets of free radical-producing myeloid-derived regulatory cells (MDRC) are master regulators of airway inflammation. They are potent modulators of both T cell responses and airway hyper-responsiveness. Dr. Deshane has identified human MDRC with similar function in bronchoalveolar lavage of asthmatics. Her current research interests are (1) to explore the free radical and cytokine/chemokine mediated mechanisms underlying the differentiation and function of myeloid derived regulatory cells in the establishment of airway inflammation and resolution of inflammation (2) to investigate MDRC- mediated regulation of the balance of Tregulatory cells and Th17 cells which control the tolerance vs inflammation (3) to understand how environmental pollutants such as tobacco smoke would impact MDRC function and contribute to exacerbation of inflammation in asthmatic smokers. These studies will provide insight into the role of MDRC in tobacco related pathology of the lung.
Charles O. Elson III, MD The central focus of the laboratory is on the regulation of mucosal immune responses, particularly the mucosal immune response to the microbiota, which represent the largest mass of antigen encountered by the immune system. The cellular and molecular mechanisms that maintain mucosal immune homeostasis are being defined. When these mechanisms fail, pathogenic effector T cells are generated that result in colitis. We have cloned a set of immunodominant antigens of the microbiota that stimulate such pathogenic T cells and result in inflammatory bowel disease. Among these cloned antigens, previously unknown bacterial flagellins have emerged as a major cluster. Seroreactivity to these flagellins is found in multiple experimental models of colitis in mice and in half of patients with Crohn's disease. These antigens drive a newly described CD4 T cell effector subset making IL-17 (Th17) which appears to be responsible for disease progression. A T cell receptor transgenic mouse reactive to CBir1 flagellin has been generated and is being used to study the innate and adaptive immune response to these microbiota antigens. A second major effort is in the identification of T reg cells in the intestine that recognize microbial antigens and maintain homeostasis. The mechanisms whereby such cells are induced are being defined and the application of these cells to prevent or treat intestinal inflammation is being tested. Lastly, a microbiota antigen microarray has been constructed which can be used to analyze serologic reactivity to the microbiota in both mouse and human. Sera from various human populations are presently being analyzed.
Jannet Katz, DDS, PhD My research program is primarily directed to understand host/microbial interactions with emphasis on the pathogens Porphyromonas gingivalis and Francisella tularensis. P. gingivalis is involved in the development of periodontal disease, a disease that has been linked to cardiovascular disorders, diabetes, rheumatoid arthritis, low weight babies and complications of patients on hemodyalisis. My studies with P. gingivalis or its purified virulence antigens are centered around the innate and T cell host responses, as well as the signaling molecules and transcription factors involved in order to develop therapies or vaccines against infection. In addition, I recently began studies on the effect of P. gingivalis infection on DNA methylation patterns in general and specifically in the obese population. The second pathogen I work with is F. tularensis, the cause of tularemia. Due to the rapid dissemination of F. tularensis by various routes, it’s ability to infect the host through various mucosal surfaces and the high virulence of some of the strains, F. tularensis is considered a bioterrorism agent. My studies with F. tularensis are geared to understand the potential of this bacterium to infect various organs/tissues, the innate and adaptive immune responses induced upon infection in the context of signaling molecules and pathways, and the potential use of rapamycin as an innovative therapy to ameliorate the infectious process by dampening an exacerbated host response.
Beatriz Leon, PhD The major research interests of the laboratory include studying the in vivo regulation of T cell responses by dendritic cells (DC), including the control of effector CD4 and CD8 T cells responses and the modulation of memory T cells. One of the lab’s major projects is to characterize the roles that DC subpopulations play in the induction of T Helper 2 (Th2) responses to common allergens that trigger allergic asthma. Infants are three to four times more prone to allergies than adults. Therefore, emphasis is placed on understanding the different molecular mechanisms involved in activation of T cells by infant and adult DC. In a second project, the lab evaluates the mechanisms determining the commitment and plasticity of memory follicular helper CD4 T cells (Tfh) cells and their role in allergy. Finally, the lab also studies how maternal alterations of bacterial microbiota affects asthma risk in offspring.
Frances E. Lund, PhD The overarching research objective of the Lund laboratory is to identify the key players that suppress or exacerbate mucosal inflammatory responses with the long-term goal of developing therapeutics to treat immunopathology associated with chronic infectious, allergic and autoimmune disease. One of the lab’s major projects is to characterize the roles that cytokine-producing “effector” B cells play in modulating inflammation and T cell-mediated immune responses to pathogens, autoantigens and allergens. In a second project, the lab evaluates how inflammatory signals regulate the balance between the development of the antibody-producing long-lived plasma cells and the memory B cell compartment within lymphoid tissues. The lab also studies how these cells are maintained long-term at inflammatory sites. Finally, the lab examines how oxidative stress induced by reactive oxygen species impacts inflammation, immune responses and cellular metabolism. In particular, the lab is experimentally modulating the NAD metabolome of immune cell in order to alter the responsiveness of these cells to oxidative stress.
Craig L. Maynard, PhD Crohn's disease and ulcerative colitis- the two main types of inflammatory bowel disease (IBD) - are believed to be due in part to a failure of intestinal immune regulation, enabling aberrant pro-inflammatory responses to the microbiota to ensue. Intestinal Treg cells are essential for promoting and maintaining intestinal immune homeostasis in the face of a complex microbiota and hold tremendous potential for therapeutic intervention/manipulation in IBD. Thus, one area of our work aims to define the cellular and molecular pathways that enhance regulatory T cell function during chronic gut inflammation. Moreover, because chronic IBD patients are at increased risk of developing colorectal cancer, ongoing studies will determine how these pathways can be manipulated to enhance anti-tumor immune responses in the lower bowel. Our second area of interest is in understanding how numerous factors related to chronic inflammatory disease impacts the long term composition and function of the intestinal microbiota. For these studies, we are utilizing gnotobiotic rodents as hosts for patient microbiota, establishing an experimental system in which to interrogate microbiota-dependent physiological responses. At present, we are investigating how dietary and genetic factors associated with chronic obesity impacts the microbial function and immmune responsiveness in the gastrointestinal tract
Jiri Mestecky, MD, PhD Molecular-cellular interactions involved in the differentiation of B lymphocytes and epithelial cells of the mucosal immune system and the novel approaches for the induction of the humoral immune response in external secretions represent the primary area of interest in our laboratory. Regulation of the expression of immunoglobulin isotypes, with emphasis on IgA and J chain synthesis, are studied in human systems under normal as well as pathologic conditions. The interactions of IgA molecules of various properties (including those found in IgA-containing immune complexes) with lymphoid cells, macrophages, hepatocytes, eosinophils, and epithelial cells are investigated in a variety of human diseases afflicting the gastrointestinal and genitourinary tracts. Development of vaccines against AIDS and sexually transmitted diseases is pursued using novel antigen delivery systems and combination of immunization routes to stimulate mucosal immunity in the genital tract.
Suzanne M. Michalek, PhD Dr. Michalek’s research program centers around two major themes; the mucosal immune system and the development of mucosal vaccines for the induction of protective immunity, and host mechanisms involved in inflammation, with emphasis on those associated with periodontal disease. Studies related to the former theme are investigating the vectors and adjuvants for the development of mucosal vaccines effective in inducing immune responses. These studies are being done in humans and experimental animal models. Current in vivo studies in humans are testing the effectiveness of mucosal vaccines consisting of a recombinant microbial polypeptide from Streptococcus mutans and adjuvants in inducing mucosal and systemic immune responses. Concurrent studies in vitro are investigating the cell surface receptor (including the co-stimulatory molecules and the Toll-like receptors) and signaling pathways involved in adjuvant activity and in the host’s recognition of the microbial virulence factor. These studies should define improved safe ways to elicit protective responses by mucosal-based vaccines. We are also using these approaches for the development of mucosal vaccines against biological threat agents. Other studies in collaboration with Dr. Noel Childers are designed to develop a childhood vaccine against dental caries. Studies are in collaboration with Drs. Jannet Katz and Ping Zhang involve immunologic, molecular biology and cell biology approaches to define microbial components and host factors involved in periodontal disease. In vivo and in vitro models are being used to define virulence factors of the periodontal pathogens, Porphrymonas gingivalis, which are likely involved in microbial adherence and invasion of the epithelial barrier. Other studies are investigating the cellular mechanisms involve in the ability of this gram-negative bacteria or its components such as lipopolysaccharide to mediate inflammatory responses. These studies also are assessing the role of the Toll-like receptors and the co-stimulatory molecules in responses. The cell types and signaling pathways involved in mediating an inflammatory response, as well as bone loss are also being investigated. Finally, studies are being performed in experimental rodent models to define the role of T cells and their cytokines in periodontitis and to develop vaccines effective in protecting against this inflammatory disease. The results of these studies should help in the development of means to treat/prevent inflammatory diseases.
Steffanie Sabbaj, PhDI am interested in studying T cells and their role in the protection, pathogenesis and transmission of various human pathogens, such as HIV-1, HCMV, Chlamydia and recently SARS-CoV-2. My focus is on different mucosal compartments with special emphasis on the female genital tract and breast milk. Our understanding of local mucosal immunity should aid in the development of preventative vaccines at mucosal surfaces. In addition, HIV-infection as a dysfunctional immunological state, can be used as a model to study human T cell immunology.
Lisa M Schwiebert, PhD The major research interests of the laboratory include studying the physiology and pathophysiology of immune responses within the lung. These interests encompass the study of respiratory disorders in order to understand the cellular and molecular mechanisms that underlie airway inflammation. On-going projects examine how surface molecules, such as CFTR and CD40, regulate the airway epithelial expression of pro-inflammatory mediators, including chemokines and adhesion molecules, that initiate and exacerbate leukocyte migration. In addition, we are examining the anti-inflammatory effects of aerobic exercise on asthma-related immune responses. Through increased understanding of the mechanisms that trigger airway inflammation, we hope to develop novel therapeutic agents that combat airway inflammatory diseases such as cystic fibrosis and asthma.
Philip D. Smith, MD Dr. Smith's laboratory investigates the gastrointestinal immune responses to infectious agents and inflammatory stimuli. The mucosal cell functions currently being investigated include macrophage anergy, T regulatory and helper cell function, virus transcytosis, and the regulation of inflammation. The cellular and molecular basis for these responses are investigated by probing purified intestinal macrophages, intestinal lymphocytes and epithelial cells with pathogens such as cytomegalovirus, HIV-1 and Helicobacter pylori or their purified or cloned products. The goal of these studies is to elucidate the cascade of events that regulate mucosal immune responses to enteric pathogens and inflammatory stimuli. Understanding these responses is critical for developing novel therapeutic agents and vaccine strategies for mucosal diseases.
Matthew Stoll, MD, PhD, MSCS My major research interest is the link between mucosal immunity and spondyloarthritis. Specifically, I am looking at the adaptive (humoral and T cell) immune responses to enteric organisms and the nature of the fecal flora in patients with spondyloarthritis. I am also interested in the epidemiology, diagnosis, and treatment of temporomandibular joint (TMJ) arthritis in children with juvenile idiopathic arthritis (JIA).