NHLBI SPECIAL EMPHASIS PANEL ON AIRWAY BIOLOGY AND DISEASE

MINUTES OF MEETING
JUNE 4-5, 1997

The meeting of the NHLBI Special Emphasis Panel on Airway Biology and Disease was convened at 6:00 p.m. on June 4, 1997 at the Chevy Chase Holiday Inn, 5520 Wisconsin Avenue, Chevy Chase, Maryland. In accordance with Public Law 92-463, the entire meeting was open to the public.

Members present: David Bassett, Ph.D.; Jack A. Elias, M.D.; Jean G. Ford, M.D.; Judith A. Foster, Ph.D.; Phyllis Gardner, M.D.; William P. Guggino, Ph.D.; Mary F. Lipscomb, M.D.; Fernando D. Martinez, M.D.; David E. Millhorn, Ph.D.; Susan Redline, M.D., Ph.D.; Robert P. Schleimer, Ph.D.; Steven D. Shapiro, M.D.; Dean Sheppard, M.D.; David P. White, M.D.; James M. Wilson, M.D., Ph.D.

Federal Employees: James P. Kiley, Ph.D. (Executive Secretary); Susan Banks-Schlegel, Ph.D.; Michele Hindi-Alexander, Ph.D.; Sri Ram, Ph.D.; Ann Rothgeb; Virginia Taggart, M.P.H.; Michael Twery, Ph.D.; Gail G. Weinmann, M.D.

Visitors: Mr. Nathaniel Polster, "HLB Newsletter".

OPEN MEETING

I. Call to Order

Dr. Kiley called the meeting to order with a statement of the purpose for the meeting: to review concepts in program areas overseen by the Airway Biology and Disease Program, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, neurobiology and sleep, and the education and training programs related to these disease areas, and to define future research directions and priorities. In addition to examining each research area separately, participants were also asked to identify research directions and scientific opportunities that would cross-cut or be common to a number of these programs.

II. Review of Confidentiality and Conflict of Interest Procedures

Dr. Kiley reviewed policies and procedures regarding confidentiality and avoidance of conflict of interest situations to members of the Committee. Committee members signed the requisite forms. III. Discussion of Proposed Concept Areas

Participants separated into working groups to extensively discuss the concepts proposed for eachof the topic areas--asthma, chronic obstructive pulmonary disease, cystic fibrosis, and neurobiology and sleep. Each group reviewed and discussed the proposed concepts within their area of focus, while also looking for cross-cutting themes. The meeting continued the next day with all participants meeting as one group. The chairperson of each working group presented a summary of the outcomes of their group's discussions and recommendations.

Areas for future research efforts include the following:

Asthma

• Investigate mechanisms of chronicity and the role of tissue remodeling in the pathogenesis of asthma;
  
  
• Examine the early life origins of asthma including early life TH1 responses, early life tissue remodeling, early life viral infections, and early life antigen exposure. It is important in these studies to differentiate whether early life events cause patients to develop asthma or whether patients who are predisposed to develop asthma respond differently in early life;
  
  
• Elucidate the pharmacogenetics of differential host response to therapeutic interventions;
  
  
• Study the natural history, risk factors, and mechanisms for difficult to treat asthmatics, near fatal and fatal asthmatics, and evaluate effects of intervention strategies;
  
  
• Pursue development of useful non-invasive imaging techniques of the airway.
  

Chronic Obstructive Pulmonary Disease and Environmental Lung Disease

COPD:

• Place more emphasis on genetic susceptibility and environmental co-factors that contribute to the development of COPD, including genetic analysis of "at risk" human populations, analysis of animal models that are resistant or susceptible, and mutational analysis of lower vertebrate species for identification of genes that are critical for injury and repair;
  
  
• Development of appropriate animal models for biochemical molecular analyses of early events leading to COPD; study progression of disease; and identify involvement of chronic bronchitis.
  

Environment:

• Determine standards for exposure and uptake that can be applicable to extrapolation modeling;
  
  
• Examine the effect of repeated exposure;
  
  
• Study effect of exposure in utero on adult function.
  

Cystic Fibrosis

• Explore the mechanisms of CFTR protein biogenesis; particularly the process of protein folding and the role of chaperones and other proteins in this process; how mis-folded mutant proteins are targeted and degraded in the endoplasmic reticulum, and how targeting of CFTR to the apical cell membrane is controlled;
  
  
• CFTR interacts with a number of other proteins. The mechanisms controlling these interactions remain obscure and represent a critical area in need of exploration.
  
  
• A particularly critical area in need of investigation is that of innate immunity (defensins, and other host-defense mechanisms) to bacterial infection, especially focussed on the mechanisms in the human airway that allow individuals to avoid bacterial colonization;
  
  
• A novel area requiring investigation is the role of modifier genes in the pathophysiology of the disease; evidence suggests that variations in these other genes influence disease expression.
  
  

Neurobiology and Sleep

Pediatric sleep disorders:

• Identify normative values for sleep and breathing parameters during sleep in asymptomatic children;
  
  
• Identify which physiological parameters best discriminate symptomatic (e.g., snoring, sleepy) children from asymptomatic children;
  
  
• Additional information about the demographic, anatomic, and pathophysiologic factors influencing the severity of obstructive sleep apnea in children is needed;
  
  
• Outcome assessment--develop tools for assessing long- and short-term outcomes of children with sleep disordered breathing (SDB);
  
  
• Assessment of quality of life in adults with mild-moderate sleep disordered breathing and the impact of SDB specific treatments (e.g. CPAP, surgery, weight loss, sleep hygiene);
  
  
• Assessment of the effect of nasal CPAP therapy on cardiovascular function in adults;
  
  
• Apply contemporary approaches to defining function in terms of basic molecular and genomic mechanisms, including development of new models using cell lines and transgenic mice, and dissection of the basic molecular organization of processes such as oxygen sensing and biological clocks.
  
  

Cross-Cutting Themes

• Determinants of lung function spanning the interuterine environment to later ages in humans and animal models. Specifically, developmental events leading to common airway diseases;
  
  
• Mechanisms of lung destruction, remodeling and repair processes in the pathogenesis of chronic lung disease. Emphasis on the central role of the epithelium in understanding lung disease;
  
  
• New approaches to study small airways;
  
  
• Environment/gene interactions;
  
  
• Disease specific methodologies including: noninvasive airway imaging, pharmacogenetics, assessing physiological function in genetically altered mouse models of airway disease.
  
  
• A full report of this meeting will be prepared and submitted to one of the respiratory journals for publication as a means of informing the scientific community of the research concepts that are considered to be of high priority by this panel of experts.
  

ADJOURNMENT

The meeting adjourned at 3:30 p.m. on June 5, 1997.

CERTIFICATION

We hereby certify that the foregoing minutes are accurate and complete.


Jack A. Elias, M.D.
Special Emphasis Panel on Airway
Biology and Disease


James P. Kiley, Ph.D.
Executive Secretary
Special emphasis Panel on Airway
Biology and Disease