University of Vermont

College of Medicine

Department of Pathology

janssen_lab

Janssen-Heininger Lab Research

Mission statement

Research: To unravel the molecular basis of diverse pulmonary diseases by emphasizing the biology of epithelial cells and redox-dependent processes.

Education: To provide an exciting research environment and extensive mentoring to all laboratory members to enable each of them to be maximally successful in the arena of biomedical sciences in diverse capacities.

Overview of current areas of research and approaches

Epithelial control of lung inflammation: The Janssen-Heininger laboratory is interested in the role of airway epithelium derived signals in the control of inflammation and remodeling. Numerous studies have demonstrated the critical role of epithelium in innate defenses to a diversity of inhaled agents and subsequent triggering of inflammation, remodeling, and potentially tumorigenesis. Extensive emphasis in our laboratory is centered around understanding the regulation of the transcription factor, Nuclear Factor kappa B (NF-kB) in airway epithelium. NF-kB activation is airways has been recently linked to the development of cancer in patients with chronic obstructive lung disease (COPD). Through implementation of transgenic approaches we have demonstrated that NF-kB activation is airway epithelium is both necessary and sufficient to drive inflammation, and regulates the interplay between innate and adaptive immunity, which is critical in promoting airway remodeling  Experiments in the laboratory also are aimed at elucidating the functional outcome of epithelial NF-kB activation in response to diverse agonists that range from nitrogen dioxide (NO2), to allergens, microbiological organisms, and agents that cause pulmonary fibrosis. We are focusing on strategies, to shut down NF-kB activation, that are based upon redox-based manipulation.

Epithelial signaling in fibrosis: Another area of focus in the Janssen-Heininger laboratory represents the mitogen activated protein kinase family member, c-Jun-N-terminal kinase (JNK), which is highly responsive to environmental stresses, such as NO2, other air pollutants and many inflammatory mediators, and plays a critical role in cell migration, apoptosis, and gene regulation. Through the use of tracheal epithelial cells that lack JNK1, we have identified that JNK1 plays a causal role in oxidant-induced cell death, and barrier disruption, and also that JNK1 promotes the expression of mesenchymal genes critical to airway remodeling. Recently, we defined that activation of JNK1 plays a critical role in epithelial-to-mesenchymal transition, a manifestation of epithelial plasticity that is believed to be critically important in tissue fibrosis and carcinogenesis. We are currently identifying the mechanism whereby JNK1 facilitates EMT and whether microRNAs are involved, and to determine the impact on fibrotic remodeling of airways.

Redox biology in environmental lung disease: Because of the marked oxidative stress that is associated with inhalation of environmental insults, inflammation, and lung cancer, the Janssen-Heininger laboratory also is actively elucidating the mechanisms whereby changes in the redox status affect the structure and function of epithelial cells. Specifically we are evaluating the impact of mild oxidants such as nitric oxide and hydrogen peroxide on the function on a variety of signaling proteins, as reversible cysteine oxidations have emerged as critical regulatory events that affect cell biology and pathophysiology. We are currently evaluating the impact of protein S-nitrosylation and protein S-glutathionylation in the regulation of NF-kB driven inflammation and death receptor induced apoptosis. Specifically we have a project aimed at determining the importance of oxidative modification of the death receptor, Fas, and the importance of those events for lung pathophysiology and fibrosis.

Technologies and functioning of the laboratory: We employ a diversity of state –of-the-art cell and molecular biological and biochemical approaches. Significant emphasis of the laboratory is centered on the 3-dimensional cultures of primary cells, in order to maximize the validity of in vitro cell based systems. We also have developed novel approaches to visualize reversible cysteine oxidations in intact cells and tissues using microscopy approaches. In collaboration with clinical investigators in the Department of Pathology and Medicine, we also are intensely investigating the extent to which redox and molecular changes occur in cells and tissue samples derived from patients with a range of pulmonary diseases. The intellectual and technical expertise in the laboratory, provided by diversely skilled post-doctoral fellows, research associates, and visiting scholars, coupled the to direct proximity with clinical investigators in the Environmental Pathology Program and Vermont Lung Center provide a rich and stimulating learning environment for students and fellows. Laboratory members have the opportunity to travel to one international conference yearly, and are required to attend weekly Environmental Pathology and Carcinogenesis, and Vermont Lung Center seminar series.

Manuscripts:

  1. Reynaert NL, van der Vliet A, Guala AS, McGovern T, Hristova M, Pantano C, Heintz NH, Heim J, Ho Y-S, Matthews DE, Wouters EFM, and Janssen-Heininger YMW: Dynamic redox control of NF-κB through glutaredoxin-regulated S-glutathionylation of inhibitory κB kinase β. Proc Natl Acad Sci U S A 103:10386-10391, 2006 PMCID: PMC1559757
  2. Pantano C, Ather JL, Alcorn JF, Poynter ME, Brown AL, Guala AS, Beuschel SL, Allen GB, Whittaker LA, Bevelander M, Irvin CG, and Janssen-Heininger YMW: Nuclear factor-κB activation in airway epithelium induces inflammation and hyperresponsiveness. Am J Respir Crit Care Med 177:959-969, 2008 PMCID: PMC2361423
  3. Anathy V, Aesif SW, Guala AS, Havermans M, Reynaert N, Ho Y-S, Budd RC, and Janssen-Heininger YMW: Redox amplification of apoptosis by caspase dependent cleavage of glutaredoxin-1 and S-glutathionylation of Fas (published w/editorial). J Cell Biol 184:241-252, 2009 PMCID: PMC2654302
  4. Aesif SW, Anathy V, Kuipers I, Guala AS, Reiss J, Ho YS, and Janssen-Heininger YMW: Ablation of glutaredoxin-1 attenuates lipopolysaccharide-induced pulmonary inflammation and alveolar macrophage activation. Am J Respir Cell Mol Biol 44:491-499, 2011 PMCID: PMC3095922
  5. Velden JL, Alcorn JF, Guala AS, Badura EC, and Janssen-Heininger YMW: c-Jun-N-terminal kinase 1 promotes TGF-(beta)1-induced epithelial to mesenchymal transition via control of linker phosphorylation and transcriptional activation of SMAD3. Am J Respir Cell Mol Biol 44:571-581, 2011 PMCID: PMC3095922

Last modified June 11 2012 12:21 PM