Project Summary/Abstract The respiratory physiology core, led by a pulmonologist clinician scientist with a special interest in respiratory physiology, performs pulmonary functional phenotyping in rodents. These measurements include awake respiratory testing, ventilated in vivo pulmonary function measurements and broncho-alveolar lavages and analysis. Early onset emphysema is the hallmark of alpha-1-antitrypsin deficiency (AATD) in humans and manifests as airway obstruction and progressive respiratory failure. AAT is a protease inhibitor that neutralizes neutrophil elastase (NE). When AAT is absent or deficient in the lungs, unopposed NE degrades and destroys the lung parenchyma and alveolar walls. This unchecked proteolytic activity leads to emphysema. Emphysema is the permanent enlargement of airspaces in the gas exchange region of the lungs. Clinically, AATD patients with emphysema have decreased pulmonary function testing, airway obstruction, decreased elastance and increased compliance. The novel AAT-KO model created here at University of Massachusetts Medical School (UMMS) provides an ideal tool to test the physiological manifestations of pulmonary disease. Preliminary testing reveals that this model does indeed have characteristic pulmonary findings similar to those seen in humans. In fact, the AAT-KO mouse has markedly increased static compliance and decreased elastance [indicative of emphysema] as well as evidence of airway obstruction. Thus, this AAT-KO model, with these clinically relevant pulmonary manifestations, provides an ideal platform to test the novel AAV and miRNA therapeutics proposed in this translational program project grant. Furthermore, the ability to assess the impact on pulmonary function and mechanics allows a better understanding of the translational potential of these therapies when they advance to clinical trials.