Respiratory diseases such as asthma, pneumonia, influenza and chronic obstructive pulmonary disease (COPD) are complex disorders that involve multiple intrinsic and extrinsic components. Important intrinsic factors that contribute to disease pathogenesis include gender, age, diet and genetic background. Extrinsic factors include exposure to environmental stimuli or triggers such as allergens, molds, air pollutants and tobacco smoke. Since complex respiratory illnesses likely result from the interaction of these variables, the Laboratory of Respiratory Biology (LRB) seeks to understand how environmental exposures influence an individual's genetic susceptibility to result in pulmonary disease pathogenesis.
The primary goals of the LRB are to:
To carry out this mission, the LRB has ten research groups headed by nine group leaders which are shown in the diagram below. Steven Kleeberger, Ph.D. is laboratory chief.
LRB research covers a wide range of studies such as the role of nuclear receptors in inflammatory sequelae or a negative after-effect of exposure, mechanisms of pulmonary fibrosis, genetic predisposition to acute lung injury and environmental asthma, and development of intervention strategies to reduce disease prevalence.
The impact of respiratory diseases in the U.S. continues to be an enormous public health concern. A 2000 report by the American Lung Association estimated that 31.3 million Americans, or 113 per 1000 persons, will develop asthma within their lifetime. Also that year, over 95 million people reported having influenza and pneumonia, and medical estimates at the time reported that 13.3 million U.S. adults had COPD. The combined number of deaths for asthma, pneumonia (the sixth leading cause) and COPD (the fourth leading cause) was 188,000. The economic cost due to morbidity and mortality of these three diseases is staggering (see chart below).
Intrinsic factors contribute to the development of respiratory diseases, and most experts agree that an individual's genetic make-up is a critical host factor in environmental and occupational disease predisposition. Numerous studies argue for a genetic basis for many lung diseases including asthma, COPD, interstitial pulmonary fibrosis (IPF) and acute respiratory distress syndrome (ARDS).
Extrinsic factors also contribute to disease pathogenesis and numerous epidemiological studies demonstrate a close association between disease morbidity/mortality and exposure. For example, asthma morbidity has been associated with exposure to the potent oxidant ozone (O3) as well as particulate matter (PM) in numerous industrial cities throughout the world. Recent work has also implicated air pollutants with increasing asthma incidence. A large body of literature also supports a number of indoor allergens as important environmental factors in allergy and asthma. These include allergens from house dust mites, molds, pets, rodents and cockroach allergen. However, not everyone responds similarly to the environmental stimuli, and intrinsic factors have been implicated as important inter-individual determinants of response.
Many respiratory experts agree that complex respiratory diseases are likely to result from interactions of susceptibility genes with multiple environmental factors. A major challenge for respiratory biologists is to understand how specific susceptibility genes and environmental exposures interact in pulmonary disease pathogenesis.
Although understanding of respiratory disease etiologies has increased, considerable work remains to be done. A complete understanding of disease pathology will emerge from integration of basic mechanistic studies with studies directed to specific diseases.
Each research group within LRB is a separate unit, with unique research goals and an independent principal investigator who directs the research activities. However, the groups have a strong history of interaction and collaboration. Investigators within each research group interact and exchange ideas, help each other in technical matters, and share equipment and reagents. LRB seminars and Work in Progress (WIP) meetings facilitate these interactions. Monthly group leaders’ meetings also foster collaborations. Collaborative studies between LRB research groups have resulted in co-authored publications and development of collaborative research programs.
Another example of interaction among LRB investigators is the Office of Translational Research (http://www.niehs.nih.gov/about/od/otr/index.cfm) initiated by a number of LRB investigators. This led to an Interagency Agreement (IAG) designed to facilitate studies conducted as a collaboration among Investigators in LRB, David Peden, M.D., from the UNC School of Medicine and Robert Devlin, Ph.D., from the Human Studies Division (HSD) of the EPA. These initial translational studies have allowed LRB investigators to combine gene discovery and mechanistic studies with clinical challenge studies in human volunteers performed by Peden and Devlin. This IAG will allow LRB investigators to test hypotheses generated by in vivo and in vitro models on human subjects.
Mentoring and Training
LRB group leaders perform several functions at the Institute, but the mentoring and training of students and postdoctoral fellows is one of the most important. Each LRB group holds weekly research meetings. The entire staff—including biologists, students and fellows—participates in the discussion and interpretation of ongoing research and the planning and design of new studies. These weekly group meetings are an essential tool for shaping a coherent and effective research team.
Additional regular informal and formal meetings ensure continued communications between the multidisciplinary investigators who comprise LRB. To this end, we have a bi-weekly LRB Seminar Series from September to June. Each group leader invites at least four speakers from outside the Institute to present formal seminars. Seminar notices circulate within the Institute and throughout Duke, UNC, NCSU and the EPA. The invited speakers generally spend at least one full day visiting with LRB group leaders and their staff. The primary objective of these seminars is to enable all LRB investigators to interact with internationally-recognized scientists and potentially develop research collaborations.
The WIP seminar series occurs on alternate weeks from September to June and rotates from one research group to another. WIP presentations have a broad format, but usually include data presentations or topical reviews. The intention is to enable all of the investigators, fellows, students and senior technicians the opportunity to present work that is ongoing and not "the finished product." This format also encourages more interaction between the speaker and the attendees and gives the presenters the opportunity to get input on experimental design, data interpretation or presentation style. These exchanges are critical to the intellectual growth and development of the laboratory and necessary to achieve and maintain high scientific quality in our research.
LRB also participates in, and jointly sponsors, the Visiting Pulmonary Scholar Program, a joint venture of the major academic, government and commercial organizations in the Research Triangle Park area that are active in pulmonary research. Eminent pulmonary scientists spend two days in the area, giving lectures and visiting with the different pulmonary research groups at NIEHS, Duke, UNC, NCSU and EPA. The invited speakers present their seminar during a special evening program at Duke that is open to all senior technical staff, graduate students and postdoctoral fellows. The evening program also includes short research presentations from two junior colleagues and a buffet dinner. This highly successful program began in 1987 and gives our young scientists an excellent opportunity to meet leaders in the field of pulmonary research and exchange ideas.
Another essential part of the training program is attendance and scientific presentations at major national meetings, including the American Thoracic Society, American Heart Association, Experimental Biology, and Gordon and Keystone Conferences. We encourage fellows, students and biologists to attend these meetings and present their work as it helps to broaden their research experience, improve their networking skills and give them national exposure.
Participation in Scientific Community Service
Each group leader also actively participates in scientific community service at the local, national and international levels. Within NIEHS, group leaders have served, or currently serve, on promotion committees (COPI, COPII, COPIII), on the institutional review board (IRB), and as members or chairs of search committees, committees for Intramural Research Awards (IRA), microarray use, etc.
At the national and international levels, LRB group leaders serve on editorial boards, as reviewers for numerous journals, and as full-time or ad hoc members of Grant Review Panels.
Group leaders have adjunct faculty appointments at Duke University, UNC, and NCSU and lecture in numerous courses offered by the institutions. They also serve as advisors for pre-doctoral candidates and sit on dissertation committees. Fessler, Schwartz and Zeldin also have clinical duties at Duke University or the Durham VA Medical Center.
LRB research covers a wide range of studies such as the role of nuclear receptors in inflammatory sequelae or a negative aftereffect of exposure, mechanisms of pulmonary fibrosis, genetic predisposition to pollutant-induced asthma, and development of methods for environmental intervention to reduce disease prevalence.
Scientific Support Staff