- COPDGene® 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease. KE Lowe, EA Regan, A Anzueto, E Austin, JHM Austin, TH Beaty, PV Benos, CJ Benway, SP Bhatt, ER Bleecker, S Bodduluri, J Bon, AM Boriek, AR Boueiz, RP Bowler, M Budoff, R Casaburi, PJ Castaldi, JP Charbonnier, MH Cho, A Comellas, D Conrad, C Davis Costa, GJ Criner, D Curran-Everett, JL Curtis, DL DeMeo, AA Diaz, MT Dransfield, JG Dy, A Fawzy, M Fleming, EL Flenaugh, MG Foreman, S Fortis, H Gebrekristos, S Grant, PA Grenier, T Gu, A Gupta, MK Han, NA Hanania, NN Hansel, LP Hayden, CP Hersh, BD Hobbs, EA Hoffman, JC Hogg, JE Hokanson, KF Hoth, A Hsiao, S Humphries, K Jacobs, FL Jacobson, EA Kazerooni, V Kim, WJ Kim, GL Kinney, H Koegler, SM Lutz, DA Lynch, Jr NR MacIntye, BJ Make, N Marchetti, FJ Martinez, DJ Maselli, AM Mathews, MC McCormack, MN McDonald, CE McEvoy, M Moll, SS Molye, S Murray, H Nath, Jr JD Newell, M Occhipinti, M Paoletti, T Parekh, M Pistolesi, KA Pratte, N Putcha, M Ragland, JM Reinhardt, SI Rennard, RA Rosiello, JC Ross, HB Rossiter, I Ruczinski, R Jose Estepar San, FC Sciurba, JC Sieren, H Singh, X Soler, RM Steiner, MJ Strand, WW Stringer, R Tal-Singer, B Thomashow, G Sánchez-Ferrero Vegas, JW Walsh, ES Wan, GR Washko, J Wells Michael, CH Wendt, G Westney, A Wilson, RA Wise, A Yen, K Young, J Yun, EK Silverman, JD Crapo. Chronic obstructive pulmonary diseases. PMID:31710793 DOI: 10.15326/jcopdf.6.5.2019.0149
- Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.
- Genome-Wide Association Study of Parametric Response Mapping in the COPDGene Study Dissects Genetic Contributions to Emphysema and Functional Small Airway Disease. CJ Benway, P Sakornsakolpat, J Ross, BD Hobbs, MH Cho, EK Silverman. American Thoracic Society. D29. LUNG MULTI-OMICS TO MECHANISM DOI: 10.1164/ajrccm-conference.2019.199.1_MeetingAbstracts.A6091
- Parametric response mapping (PRM) of paired lung computed tomography (CT) scans has improved assessment and characterization of chronic obstructive pulmonary disease (COPD), allowing for the quantification of two distinct components that contribute to airflow obstruction: emphysema and functional small airway disease (fSAD). Previously, genome-wide association studies (GWAS) of quantitative imaging phenotypes have identified genetic variants associated with emphysema and gas trapping, several of which are also associated with COPD susceptibility and lung function levels. We hypothesized that the improved quantitative resolution of PRM would reveal novel genetic association signals distinct to each phenotypic component.
- Genetic Advances in COPD: Insights from COPDGene. MF Ragland*, CJ Benway*, SM Lutz, RP Bowler, J Hecker, JE Hokanson, JD Crapo, PJ Castaldi, DL DeMeo, CP Hersh, BD Hobbs, C Lange, TH Beaty, MH Cho, EK Silverman. American Journal of Respiratory and Critical Care Medicine. PMID: 30908940 DOI: 10.1164/rccm.201808-1455SO
- Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Fortunately, over the past decade, the proliferation of genome-wide association studies (GWAS), the accessibility of whole genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in our understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene, a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-GWAS analysis.
- Defining a microRNA‐mRNA interaction map for calcineurin inhibitor induced nephrotoxicity. CJ Benway, J Iacomini. American Journal of Transplantation. PMID: 28925592 DOI: 10.1111/ajt.14503
- Calcineurin inhibitors induce nephrotoxicity through poorly understood mechanisms thereby limiting their use in transplantation and other diseases. Here we define a microRNA (miRNA)‐messenger RNA (mRNA) interaction map that facilitates exploration into the role of miRNAs in cyclosporine‐induced nephrotoxicity (CIN) and the gene pathways they regulate. Using photoactivatable ribonucleoside‐enhanced crosslinking and immunoprecipitation (PAR‐CLIP), we isolated RNAs associated with Argonaute 2 in the RNA‐induced silencing complex (RISC) of cyclosporine A (CsA) treated and control human proximal tubule cells and identified mRNAs undergoing active targeting by miRNAs. CsA causes specific changes in miRNAs and mRNAs associated with RISC, thereby altering post‐transcriptional regulation of gene expression. Pathway enrichment analysis identified canonical pathways regulated by miRNAs specifically following CsA treatment. RNA‐seq performed on total RNA indicated that only a fraction of total miRNAs and mRNAs are actively targeted in the RISC, indicating that PAR‐CLIP more accurately defines meaningful targeting interactions. Our data also revealed a role for miRNAs in calcineurin‐independent regulation of JNK and p38 MAPKs caused by targeting of MAP3K1. Together, our data provide a novel resource and unique insights into molecular pathways regulated by miRNAs in CIN. The gene pathways and miRNAs defined may represent novel targets to reduce calcineurin induced nephrotoxicity.
- Defining a microRNA-mRNA targetome for calcineurin inhibitor induced nephrotoxicity CJ Benway. ProQuest Dissertations and Theses ISBN: 9780355361575
- The use of calcineurin inhibitors has revolutionized solid organ transplantation increasing survival rates dramatically. However, calcineurin inhibitor induced nephrotoxicity severely limits the use of this class of drugs in transplantation and other diseases. Here we set out to define a microRNA (miRNA)-messenger RNA (mRNA) interaction map to identify the role of miRNAs in cyclosporine-induced nephrotoxicity and the gene pathways they regulate. By integrating miRNA and mRNA expression profiling with photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) against endogenous Argonaute 2 (AGO2) protein in human proximal tubule cells, we identified miRNAs and mRNAs undergoing active targeting in cyclosporine A (CsA) treated cells and vehicle-treated controls. First, expression profiling of miRNAs and mRNAs in CsA-treated versus vehicle-treated cells identified the key canonical pathways and cellular processes which are dysregulated in proximal tubule epithelial cells (PTECs) by CsA. Our data support a model whereby CsA induces and epithelial-to-mesenchymal-like (EMT-like) re-programming of PTECs by down-regulation of key apical surface, cell junction, and adherens junction genes as well as up-regulation of major pro-EMT cell signaling pathways such as PI3K/AKT, ERK, and TGF-β. Our data indicate that CsA causes specific changes in miRNAs and mRNAs associated with the RNA-Induced Silencing Complex (RISC) complex. Pathway enrichment analysis identified canonical pathways specifically under regulation by miRNAs following CsA treatment. Analysis of active miRNA-mRNA targeting interactions revealed that CsA suppresses an upstream regulator of JNK and p38 MAPKs by inducing targeting of MAP3K1 by miR-101-3p thereby uncovering a previously undefined mechanism by which CsA affects calcineurin-independent molecular pathways. These insights into the molecular pathways governing expression of genes involved in cyclosporine-induced nephrotoxicity may provide novel therapeutic approaches to preventing chronic renal injury in transplant recipients.
- MicroRNA‐494 Promotes Cyclosporine‐Induced Nephrotoxicity and Epithelial to Mesenchymal Transition by Inhibiting PTEN. J Yuan, CJ Benway, J Bagley, J Iacomini. American Journal of Transplantation. PMID: 25854542 DOI: 10.1111/ajt.13161
- A major complication associated with cyclosporine (CsA) treatment is nephrotoxicity. In this study, we examined whether microRNAs play a role in cyclosporine-induced nephrotoxicity. Treatment of mice with CsA resulted in nephrotoxicity that was associated with an early increase in expression of microRNA mmu-miR-494 (miR-494). Similarly, tubular epithelial cell epithelial-mesenchymal transition (EMT) induced by CsA toxicity resulted in the upregulation of microRNA-494 and a decrease in PTEN levels in vitro. miR-494 directly targeted Pten and negatively regulated its expression. Preventing Pten targeting by miR-494 was sufficient to prevent CsA induced EMT. Knockdown of miR-494 prevented the downregulation of PTEN in tubular epithelial cells following CsA treatment and also prevented CsA induced EMT. Thus, miR-494 plays a major role in promoting CsA induced nephrotoxicity through its ability to target Pten thereby contributing to EMT. We suggest that manipulating miR-494 expression may represent a novel approach to preventing EMT associated with CsA induced nephrotoxicity.
- The capacity for nitrate regulation of root hydraulic properties correlates with species’ nitrate uptake rates A Górska, JW Lazor, AK Zwieniecka, CJ Benway, MA Zwieniecki. Plant and soil. DOI: 10.1007/s11104-010-0540-x
- A mechanism whereby water flow towards root surfaces is stimulated when exposed to nutrient patches may be evolutionarily desirable in environments with heterogeneous soils. Indeed, the presence of nitrate has been shown to increase root hydraulic conductance in a few agricultural species characterized by high nitrate demand. Does a similar stimulation of root conductivity in response to external nitrate addition exist among wild type organisms? To answer this question, we studied and compared the effect of a sudden increase of nitrate concentration on root hydraulic properties in seven species. These included three agricultural species (Cucumis sativus L., Solanum esculentum L., Zea mays L.) and four wild type species (Arabidopsis thaliana L., Festuca arundinacea Schreb., Populus trichocarpa Torr.&Gray, Nephrolepis exaltata L.). The selected species differed in overall nitrate demand and specific nitrate uptake rates. Changes in root hydraulic conductance induced by nitrate varied from non-existent (N. exaltata L.) to more than 50% increases (Z. mays L.). The magnitude of the hydraulic response to nitrate presence was significantly correlated with species nitrate uptake rate. This finding suggests an emergent physiological trait that links together plant nitrate needs, nitrate availability and root hydraulic properties.