DESCRIPTION (provided by applicant): Robert L. Owens, MD is a clinical and research fellow in the Divisions of Sleep and Pulmonary/Critical Care Medicine at the Brigham and Women's Hospital. He has a background in Chemical Engineering, Internal Medicine, Pulmonary and Critical Care, and Sleep Medicine. His research efforts have focused on respiratory mechanics, with two projects to date resulting in first author publications. The most recent work quantified the influence of lung volumes on upper airway collapsibility, and helps explain the role of lung volumes in obstructive sleep apnea. Completion of the project required careful measurements made during sleep using techniques perfected in the lab of Dr. Atul Malhotra, the proposed mentor. Using some of these tools, Dr. Owens will now focus on respiratory mechanics during sleep in patients with asthma and study the pathogenesis of nocturnal asthma. He will test the hypotheses that 1) lung volumes are important in lower airway mechanics in people with asthma, and 2) that manipulation of lung volumes (using positive airway pressure) will improve nocturnal asthma severity. Although prior work has been done in this area, methodological issues may have contributed to some of the negative prior results. In order to accomplish this task, further training in respiratory mechanics, statistics, and clinical trial design will be necessary. A mentored K23 grant will provide the support necessary to pursue the ongoing training and research. Ultimately, the career development grant will form the foundation for Dr. Owens to become a successful independent investigator. Environment Dr. Atul Malhotra will serve as Dr. Owens's mentor. Dr. Malhotra has a proven track record of research, obtaining considerable independent funding, and development of junior faculty. His laboratory is known for obtaining physiological data in heavily instrumented, yet sleeping, subjects. His laboratory has ongoing collaborations with renowned respiratory physiologists (such as Drs. Steven Loring and Jeffrey Fredberg), and asthma clinical researchers (Dr. Jeffrey Drazen and the Asthma Clinical Research Network). Furthermore, James Butler, another expert in respiratory physiology has recently joined the lab. The Brigham and Women's Hospital is in close proximity to the Harvard School of Public Health and the Beth Israel Deaconess Medical Center, among others, which provides a rich intellectual environment. The BWH is committed to training future physician-scientists, and provides training in many areas, including the responsible conduct of research. Research Asthma is a chronic respiratory disease characterized by airway inflammation and airway hyper- responsiveness, which causes airflow obstruction. It is extremely prevalent, affecting an estimated 22 million Americans, and costly with loss of productivity and direct healthcare costs in the billions of dollars. The incidence and prevalence of asthma are increasing, both in the US and around the world. This increase comes despite greater understanding of the inflammatory and allergic basis for asthma, and despite better anti- inflammatory medications. One explanation for the increasing prevalence of asthma is the concomitant increase in obesity, with the majority of Americans now overweight or obese. Numerous studies have convincingly linked asthma and obesity, and demonstrated increased obstruction with weight gain and decreased obstruction with weight loss. However, the mechanisms that underlie this linkage are not known. We believe that low lung volumes contribute to the pathogenesis and severity of asthma. End-expiratory lung volume is decreased in obesity, and likely falls further during sleep, particularly in overweight and obese patients. Both upper and lower airway resistance increase with decreasing lung volumes, as airways become smaller. However, prior work has shown that lower airway resistance increases out of proportion to the decrease in lung volume that occurs during sleep in asthma patients. This difference between controls and people with asthma has not been further explored, yet may provide insight into asthma pathogenesis and provide potential targets for therapy. Therefore, we propose a series of experiments to define the impact of lung volumes during sleep on airway resistance. Methodologies already in use in our lab will be applied to patients with asthma and controls. Nocturnal airway resistance will be measured continuously using the forced oscillation technique (FOT), a non- invasive measurement that is ideal for use during sleep. Lung volumes can be monitored with magnetometers, and esophageal manometry will be used to estimate transpulmonary pressures. Finally, we will test the hypothesis that lung stretch can be used therapeutically by tonically and dynamically increasing lung volumes during sleep using bi-level positive airway pressure. This research can help delineate asthma pathogenesis and may help improve therapeutic options in this exceedingly common disease.

Asthma is an extremely common disorder, which is becoming more prevalent. The purpose of this study is to examine how nocturnal lung volumes contribute to asthma severity, which may explain part of the link between asthma and obesity. Our work may lead to new targets for therapy.