Chronic obstructive pulmonary disease (COPD) is the 3rd-leading cause of death in the US, generally due to cigarette smoking. Current treatments, including smoking cessation after the very earliest stages, provide only short-term benefit and cannot stop its inexorable progression. Novel therapies to halt progression are thus urgently needed. COPD pathophysiology includes bronchial inflammation and septal destruction leading to emphysema, with such septal destruction caused by inflammation-associated oxidative stress and protease secretion. Based on promising preliminary findings, the proposed research will test the beneficial role in COPD and mechanisms that regulate farnesoid X receptor (FXR), a nuclear hormone receptor whose roles in lungs and COPD are unknown. Preliminary studies revealed FXR is downregulated in airway epithelial cells (AECs) of COPD patients and in mice with cigarette smoke (CS)-induced COPD, and that CS elicits such FXR downregulation in vitro, leading us to hypothesize that FXR downregulation in patients contributes to COPD pathogenesis. We also found that FXR knockout (KO) exacerbates CS-induced inflammation and emphysematous lung damage in mice, whereas stimulating FXR by treating mice with FXR agonist during smoke exposure blocked these effects, suggesting FXR agonists may be useful for COPD therapy. Mechanistic studies of CS-induced FXR downregulation suggest it is mediated by ubiquitination and proteasomal degradation, triggered by binding of an E3-ligase containing a specific F-box protein. Further preliminary findings indicate that binding of an FXR agonist blocked this by promoting binding of the peptydylprolyl isomerase Pin1, because the F-box protein was unable to bind to the resulting cis-Pro form of FXR. Based on these novel findings, the specific aims are: 1: To determine whether the suppression of FXR activity that occurs in COPD promotes COPD progression and severity and the mechanisms driving such suppression; and 2: To test whether activating FXR, specifically in AECs or generally in lung, ameliorates COPD severity and progression and the mechanisms by which agonists block FXR degradation. To achieve these aims we will utilize novel transgenic mice in which FXR is deleted or constitutively active specifically in AECs and in vitro studies utilizing FXR or F-box protein constructs carrying mutations at sites believed to be crucial for their interaction. The results will determine the pathogenic role in COPD of a previously-overlooked receptor, and the opposing mechanisms by which CS promotes its degradation but agonists stabilize it. They may also identify FXR as a promising new therapeutic target for a widespread fatal disease.
No current therapy prevents the inexorable progression of chronic obstructive pulmonary disease (COPD), the 3rd-leading cause of death in the US. Dysregulated inflammation drives COPD pathogenesis, but the role of the anti-inflammatory receptor farnesoid X receptor (FXR) in COPD is unknown. Based on promising evidence, we will test whether the degradation of FXR that we found occurs in COPD contributes to COPD development and progression, and whether activating FXR with drugs provides therapeutic benefit and slows progression.
| Banno, Asoka; Reddy, Aravind T; Lakshmi, Sowmya P et al. (2018) PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma. Nucl Receptor Res 5: |
| Reddy, Aravind T; Lakshmi, Sowmya P; Banno, Asoka et al. (2018) Identification and Molecular Characterization of Peroxisome Proliferator-Activated Receptor ? as a Novel Target for Covalent Modification by 15-Deoxy-?12,14-prostaglandin J2. ACS Chem Biol : |
| Reddy, Aravind T; Lakshmi, Sowmya P; Banno, Asoka et al. (2018) Role of GPx3 in PPAR?-induced protection against COPD-associated oxidative stress. Free Radic Biol Med 126:350-357 |
| Lakshmi, Sowmya P; Reddy, Aravind T; Banno, Asoka et al. (2018) Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor ? Regulates Inflammation and Mucin Expression in Allergic Airway Disease. J Immunol 201:1775-1783 |
