Abstract NF-B plays a causative role in the inflammation and pathogenesis of various diseases such as lung disease, the third leading killer in the United States responsible for one in seven deaths. However, we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology, and in particular, innate immunity and host defense. Teasing apart these functions of NF-B will overcome this barrier resulting in a powerful means to fight lung and other diseases. Although the core mechanism driving NF-B activation has been well defined and is the same under most physiological and pathogenic conditions, the mechanistic difference in physiologic versus pathogenic NF-B remains largely unknown. Recently, we have demonstrated, for the first time, that NF-B exhibits different activation patterns in normal and malignant lung epithelial cells, the first line of defense and a key component of the innate immunity in the lung. Furthermore, we have revealed, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 as a tumor suppressor and ubiquitin E3 ligase that selectively degrades the ‘pathogenic’ form but not the ‘physiologic’ form of NF-B (thereby preventing pathogenic activation while allowing physiologic activation of NF-B by inflammatory stimuli) and can be targeted as mono- or combination therapy in authentic mouse models of human lung cancer. Like in human lung cancer, of note, PDLIM2 is repressed in the lungs of patients with chronic obstructive pulmonary disease (COPD) or interstitial lung diseases (ILDs), and PDLIM2 repression is associated with disease severity and poor patient survival. Lung epithelial-specific or global deletion of PDLIM2 renders mice highly susceptible to spontaneous and induced lung cancers as well as acute lung injury and death by the bacteria endotoxin lipopolysaccharide (LPS). Based on these trailblazing discoveries, in this proposal we will identify the functional partners of PDLIM2 and determine the structural and biochemical mechanisms by which they act as a ubiquitin E3 ligase complex to dichotomize the differential activation of NF-B in lung epithelial cells. We will also determine in vivo and in vitro the roles and molecular mechanisms of this regulation in lung disease and host defense against pulmonary infection using conditional and inducible knockout (KO) or knock-in (KI) mice and cells of PDLIM2 and/or NF-B. These studies will improve our understanding of normal lung physiology and pulmonary diseases, and open new avenues to study NF-B regulation and action. They may also lead to new clinically feasible approaches to selectively target pathogenic NF-B and reveal new therapeutic targets for better lung disease treatment.