The goal of this application is to support the career development of Dr. John Sundy so that at the completion of the award he will be an independent researcher and outstanding academic clinician-scientist in the field of environmental airway disease. Dr. David Schwartz will assume responsibility as mentor to ensure the success of the career development plan. The foundation of this proposal is an extensive mentored research training experience in the genetic epidemiology of environmental asthma. The training process will comprise didactic course work in clinical research methodology, genetics and genetic epidemiology; mentoring by Dr. Marcy Speer in genetic analysis methods; and completion of a research project. Dr. Schwartz will supervise Dr. Sundy in completing a research project aimed at characterizing defects in immune responses to lipopolysaccharide (LPS) in individuals with mutations in the gene for Toll-like receptor 4 (TLR4), an LPS receptor. LPS is an important component of grain dusts and other environmental bioaerosols that cause airway inflammation and airflow obstruction; and is thought to be important in the pathogenesis of environmental asthma. The candidate's laboratory has shown that common cosegregating mutations in TLR4 are associated with reduced airway responsiveness to inhaled LPS. An important unanswered question is whether mutations in TLR4 affect LPS induced immune responses in humans and, if so, whether these changes in immunity underlie the physiologic alterations in LPS responsiveness among TLR4 mutant individuals. They hypothesize that individuals with the co-segregating Asp299GIy and Thr3991le mutations in the TLR4 gene will exhibit a defective immune response to LPS, and that specific components of altered immunity in these individuals are linked to characteristic airway responses to LPS. To test this hypothesis, Dr. Sundy will identify healthy, non-asthmatic individuals with the co-segregating Asp299GIy and Thr399Ile TLR4 mutations or individuals who are wild type for TLR4, and compare their response to in vitro and in vivo LPS challenge. LPS-induced immune responses will be compared to LPS-induced changes in airflow obstruction to identify potential mechanisms linking immunity to physiology. These studies will help determine the mechanisms by which an important gene-environment interaction (TLR4 and endotoxin) contributes to the pathogenesis of environmental asthma. Dr. Sundy will perform these studies with the mentoring of Drs. Schwartz and Speer. He will have access to the resources of Duke, including the Center for Human Genetics, the Duke Clinical Research Institute, and the General Clinical Research Center to carry out his career development plan. Both the mentor and the institution are highly committed to Dr. Sundy's career development and academic success.