Asthma is a chronic inflammatory disease that poses a significant public health problem affecting approximately 13% of U.S. adults. Individuals with asthma have a two-fold higher risk of developing a mood or anxiety disorder than those without asthma and this co-morbidity is associated with poorer asthma control, increased symptom frequency, and more physician and emergency room visits. Yet research directed at understanding asthma pathophysiology and treatment has neglected the role of the brain almost entirely. The proposed research, therefore, will examine the neural underpinnings of the influence of psychological factors on asthma-relevant physiology. The primary objectives of these projects are to (1) elucidate the neural circuitry through which chronic psychosocial stress influences the inflammatory response in asthma (2) quantify the impact of chronic stress on objective measures of lung function and inflammation and (3) evaluate the impact of neural changes, accrued through training in mindfulness, to alter the impact of chronic stress on the development of airway inflammation. To accomplish these objectives, asthmatic individuals with and without significant chronic life stress, as well as healthy non-asthmatic controls with and without chronic life stress, will be recruited for study. All participants will perform a psychosocial stress test. Positron emission tomography (PET) will be used to measure the neural response to the stressor, such that uptake of radiolabeled glucose will take place during performance of the stress task. PET data (glucose metabolic rate) collected after completion of the task will reflect the relative neural activity that occurred during task performance. Glucose metabolic rate will be examined in relation to measures of lung function (FEV1), inflammation (sputum and blood eosinophils, exhaled nitric oxide), sensitivity of immune cells to inhibition by glucocorticoids, stress responsivity (salivary cortisol and alpha amylase), self-reported asthma symptom control, and self-reported psychological factors (e.g. depression and anxiety). Differences in stress-induced glucose metabolic rate in high versus low chronically stressed asthmatics and controls will be characterized. In addition, the peripheral physiological measures will be examined on their own, and in relation to changes in glucose metabolic rate, to quantify the impact of chronic stress on physiological measures of import to asthma. These data will provide the basis for a subsequent intervention study that addresses objective 3. Training in mindfulness meditation will be evaluated for its ability to impact the effects of chronic stress on the factors that underlie asthma symptom expression. The protocol described above will be employed before participants receive mindfulness training and again following completion of training, in order to examine changes that may occur in the neural response to stress that underlie potential symptom alleviation associated with mindfulness training. The immediate goal of the candidate, Dr. Melissa Rosenkranz, is to understand the neural mechanisms through which chronic stress regulates inflammatory processes in asthma and through which the pathophysiology of asthma promotes mood and anxiety disorders. Her long-term goal is to generalize this aim; to bring to light the mechanisms and pathways through which mental events lead to disease expression and progression, and through which peripheral disease expression causes cognitive and emotional changes. By extension, Melissa hopes to contribute to new ways of approaching healthcare and management of disease, where the brain is featured prominently. Melissa is uniquely situated to successfully carry out the proposed research and to realize these goals. She has already demonstrated her ability to execute highly complex and collaborative research projects of this nature, as is evident in her strong publication record. Nonetheless, interdisciplinary research poses a significant challenge to young scientists. To pursue these goals with the utmost rigor requires expertise in not one, but at least three distinct methodological domains: psychology, neuroscience, and immunology. Typically, a student would spend several years becoming an expert in any one of these domains. Thus far, her training has focused primarily on methods in the first two. A career development award will provide the protected time, resources, and formal structure for Melissa to greatly expand her expertise in immunology and neuroanatomy via formal mentorship and advisory relationships, and to add a new neuroimaging modality (PET) to her repertoire of tools. In addition, she will receive training in and support for a key component of her long-term goal: to determine how changing neural function, through mental training techniques, impacts the relationship between psychological events and disease expression. Melissa's sponsor, Dr. Richard Davidson, and co-sponsor, Dr. William Busse offer unparalleled expertise, training opportunities, and resources with which Melissa can flourish as a young investigator in addressing questions of significant public health importance. Her questions are tractable and her research resubmission and training objectives are bold and innovative. The combination of expertise that she brings to this opportunity and the expertise and resources that her team of mentors and advisors can impart to her creates an ideal scenario for Melissa to make substantial contributions to this field.