- Research Assistant Professor, Medicine
- Ph.D. Clinical Translationa Sciences
- University of Arizona, Tucson, Arizona, United States
- MOLECULAR STRATEGIES TO DISTINGUISH KEY SUBPHENOTYPES IN SARCOIDOSIS
- MPH Public Health
- Benedictine University, Lisle, Illinois, United States
- M.D. Medicine
- Universidad Autonoma de Aguascalientes, Aguascalientes, Mexico
- Clinical Translational Sciences Travel Award
- University of Arizona, Summer 2019
- Clinical Translational Sciences Travel Award.
- CTS Graduate Program, Summer 2018
Licensure & Certification
- Medical Graduate, Educational Commission for Foreign Medical Graduates (2009)
ClinicalResearch. Interstitial Lung diseases/ Sarcoidosis.
No activities entered.
- Casanova, N. (2016). Health Disparities in Respiratory Medicine. New York: Humana Press. doi:10.1007/978-3-319-23675-9
- Casanova, N. G., Zhou, T., Gonzalez-Garay, M. L., Lussier, Y. A., Sweiss, N., Ma, S. F., Noth, I., Knox, K. S., & Garcia, J. G. (2021). MicroRNA and protein-coding gene expression analysis in idiopathic pulmonary fibrosis yields novel biomarker signatures associated to survival. Translational research : the journal of laboratory and clinical medicine, 228, 1-12.More infoIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology that poses significant challenges in early diagnosis and prediction of progression. Analyses of microRNA and gene expression in IPF have yielded potentially predictive information. However, the relationship between microRNA/gene expression and quantitative phenotypic value in IPF remains controversial, as is the added value of this approach to current molecular signatures in IPF. To identify biomarkers predictive of survival in IPF via a microRNA-driven strategy. We profiled microRNA and protein-coding gene expression in peripheral blood mononuclear cells from 70 IPF subjects in a discovery cohort. We linked the microRNA/gene expression level with the quantitative phenotypic variation in IPF, including diffusing capacity of the lung for carbon monoxide and the forced vital capacity percent predicted. In silico analyses of expression profiles and quantitative phenotypic data allowed the generation of 2 sets of IPF molecular signatures (unique for microRNAs and protein-coding genes) that predict IPF survival. Each signature performed well in a validation cohort comprised of IPF patients aggregated from distinct patient populations recruited from different sites. Resampling test suggests that the protein-coding gene based signature is comparable and potentially superior to published IPF prognostic gene signatures. In conclusion, these results highlight the utility of microRNA-driven peripheral blood molecular signatures as valuable and novel biomarkers associated to individuals at high survival risk and for potentially facilitating individualized therapies in this enigmatic disorder.
- Bime, C., Camp, S. M., Casanova, N., Oita, R. C., Ndukum, J., Lynn, H., & Garcia, J. G. (2020). The acute respiratory distress syndrome biomarker pipeline: crippling gaps between discovery and clinical utility. Translational research : the journal of laboratory and clinical medicine, 226, 105-115.More infoRecent innovations in translational research have ushered an exponential increase in the discovery of novel biomarkers, thereby elevating the hope for deeper insights into "personalized" medicine approaches to disease phenotyping and care. However, a critical gap exists between the fast pace of biomarker discovery and the successful translation to clinical use. This gap underscores the fundamental biomarker conundrum across various acute and chronic disorders: how does a biomarker address a specific unmet need? Additionally, the gap highlights the need to shift the paradigm from a focus on biomarker discovery to greater translational impact and the need for a more streamlined drug approval process. The unmet need for biomarkers in acute respiratory distress syndrome (ARDS) is for reliable and validated biomarkers that minimize heterogeneity and allow for stratification of subject selection for enrollment in clinical trials of tailored therapies. This unmet need is particularly highlighted by the ongoing SARS-CoV-2/COVID-19 pandemic. The unprecedented numbers of COVID-19-induced ARDS cases has strained health care systems across the world and exposed the need for biomarkers that would accelerate drug development and the successful phenotyping of COVID-19-infected patients at risk for development of ARDS and ARDS mortality. Accordingly, this review discusses the current state of ARDS biomarkers in the context of the drug development pipeline and highlight gaps between biomarker discovery and clinical implementation while proposing potential paths forward. We discuss potential ARDS biomarkers by category and by context of use, highlighting progress in the development continuum. We conclude by discussing challenges to successful translation of biomarker candidates to clinical impact and proposing possible novel strategies.
- Bime, C., Casanova, N. G., Nikolich-Zugich, J., Knox, K. S., Camp, S. M., & Garcia, J. G. (2020). Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury. Translational research : the journal of laboratory and clinical medicine.More infoApproximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.
- Casanova, N. G., Gonzalez-Garay, M. L., Sun, B., Bime, C., Sun, X., Knox, K. S., Crouser, E. D., Sammani, N., Gonzales, T., Natt, B., Chaudhary, S., Lussier, Y., & Garcia, J. G. (2020). Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas. Translational Research, 21(1), 321.More infoDespite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures.
- Sun, B. L., Sun, X., Casanova, N., Garcia, A. N., Oita, R., Algotar, A. M., Camp, S. M., Hernon, V. R., Gregory, T., Cress, A. E., & Garcia, J. G. (2020). Role of secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in prostate cancer progression: Novel biomarker and therapeutic target. EBioMedicine, 61, 103059.More infoThere remains a serious need to prevent the progression of invasive prostate cancer (PCa). We previously showed that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator via TLR4 ligation which has been implicated in PCa progression. Here we investigate the role of eNAMPT as a diagnostic biomarker and therapeutic target in the progression of PCa.
- Sun, X., Sun, B. L., Babicheva, A., Vanderpool, R., Oita, R. C., Casanova, N., Tang, H., Gupta, A., Lynn, H., Gupta, G., Rischard, F., Sammani, S., Kempf, C. L., Moreno-Vinasco, L., Ahmed, M., Camp, S. M., Wang, J., Desai, A. A., Yuan, J. X., & Garcia, J. G. (2020). Direct Extracellular NAMPT Involvement in Pulmonary Hypertension and Vascular Remodeling. Transcriptional Regulation by SOX and HIF-2α. American journal of respiratory cell and molecular biology, 63(1), 92-103.More infoWe previously demonstrated involvement of (nicotinamide phosphoribosyltransferase) in pulmonary arterial hypertension (PAH) and now examine regulation and extracellular NAMPT's (eNAMPT's) role in PAH vascular remodeling. transcription and protein expression in human lung endothelial cells were assessed in response to PAH-relevant stimuli (PDGF [platelet-derived growth factor], VEGF [vascular endothelial growth factor], TGF-β1 [transforming growth factor-β1], and hypoxia). Endothelial-to-mesenchymal transition was detected by SNAI1 (snail family transcriptional repressor 1) and PECAM1 (platelet endothelial cell adhesion molecule 1) immunofluorescence. An eNAMPT-neutralizing polyclonal antibody was tested in a PAH model of monocrotaline challenge in rats. Plasma eNAMPT concentrations, significantly increased in patients with idiopathic pulmonary arterial hypertension, were highly correlated with indices of PAH severity. eNAMPT increased endothelial-to-mesenchymal transition, and each PAH stimulus significantly increased endothelial cell promoter activity involving transcription factors STAT5 (signal transducer and activator of transcription 5), SOX18 (SRY-box transcription factor 18), and SOX17 (SRY-box transcription factor 17), a PAH candidate gene newly defined by genome-wide association study. The hypoxia-induced transcription factor HIF-2α (hypoxia-inducible factor-2α) also potently regulated promoter activity, and HIF-2α binding sites were identified between -628 bp and -328 bp. The PHD2 (prolyl hydroxylase domain-containing protein 2) inhibitor FG-4592 significantly increased promoter activity and protein expression in an HIF-2α-dependent manner. Finally, the eNAMPT-neutralizing polyclonal antibody significantly reduced monocrotaline-induced vascular remodeling, PAH hemodynamic alterations, and NF-κB activation. eNAMPT is a novel and attractive therapeutic target essential to PAH vascular remodeling.
- Bime, C., & Casanova, N. (2019). Development of a biomarker mortality risk model in acute respiratory distress syndrome. Critical Care, 23(410). doi:doi:10.1186/s13054-019-2697-x
- Bime, C., Casanova, N., Oita, R. C., Ndukum, J., Lynn, H., Camp, S. M., Lussier, Y., Abraham, I., Carter, D., Miller, E. J., Mekontso-Dessap, A., Downs, C. A., & Garcia, J. G. (2019). Development of a biomarker mortality risk model in acute respiratory distress syndrome. Critical care (London, England), 23(1), 410.More infoThere is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome.
- Casanova, N., Zhou, T., Garcia, J. G., & Gonzalez-Garay, M. L. (2019). Low Dose Carbon Monoxide Exposure in Idiopathic Pulmonary Fibrosis Produces a CO Signature Comprised of Oxidative Phosphorylation Genes. Scientific Reports. doi:10.1038/s41598-019-50585-3.More infoWe recently reported the results of a multicenter, double-blinded, clinical trial of inhaled CO in patients with idiopathic pulmonary fibrosis (IPF). Despite modest increases in CO blood levels, low dose CO exposure failed to demonstrate a significant effect on the primary study endpoint of changes in serum metalloproteinase-7 (MMP7), or secondary endpoints of physiologic measures, hospitalization, death, or patient-reported outcomes. In the present study, we evaluated the effect of CO exposure (12 week treatment) on genome-wide gene expression in peripheral blood mononuclear cells (PBMC) derived from these IPF study subjects.We identified a clear CO signature dominated by significant dysregulation of genes in the oxidative phosphorylation pathway. These findings suggest this signature may serve as a potential genomic biomarker for CO exposure and perhaps for titration of dosage to allow precision testing of therapies in future low dose CO therapeutic studies in IPF.
- Casanova, N., Zhou, T., Gonzalez-Garay, M. L., Rosas, I. O., Goldberg, H. J., Ryter, S. W., Collard, H. R., El-Chemaly, S., Flaherty, K. R., Hunninghake, G. M., Lasky, J. A., Lederer, D. J., Machado, R. F., Martinez, F. J., Noth, I., Raghu, G., Choi, A. M., & Garcia, J. G. (2019). Low Dose Carbon Monoxide Exposure in Idiopathic Pulmonary Fibrosis Produces a CO Signature Comprised of Oxidative Phosphorylation Genes. Scientific reports, 9(1), 14802.More infoCompelling preclinical studies indicate that low-dose carbon monoxide (CO) abrogates experimental lung fibrosis. We recently reported the results of a multicenter, double-blinded, clinical trial of inhaled CO in patients with idiopathic pulmonary fibrosis (IPF). Identifying no significantly changes in metalloproteinase-7 (MMP7) serum concentration, or secondary endpoints of physiologic measurements, hospitalization, death, or patient-reported outcomes. In the present study, we evaluated the effect of low dose CO exposure (100-200 ppm) for 12 weeks on genome-wide gene expression in peripheral blood mononuclear cells (PBMC) derived from these IPF study subjects. We conducted transcriptome profiling on 38 IPF subjects with time points available at 0, 12, and 24 weeks. Total RNA isolated from PBMCs was hybridized onto the Affymetrix Human Gene 2.0 ST Array. We identified 621 genes significantly upregulated in the 24-week CO exposed group compared with the 12-week. Pathway analysis demonstrated association with Oxidative Phosphorylation (adjusted P
- Lynn, H., Sun, X., Casanova, N., Gonzales-Garay, M., Bime, C., & Garcia, J. G. (2019). Genomic and Genetic Approaches to Deciphering Acute Respiratory Distress Syndrome Risk and Mortality. Antioxidants & redox signaling, 31(14), 1027-1052.More infoAcute respiratory distress syndrome (ARDS) is a severe, highly heterogeneous critical illness with staggering mortality that is influenced by environmental factors, such as mechanical ventilation, and genetic factors. Significant unmet needs in ARDS are addressing the paucity of validated predictive biomarkers for ARDS risk and susceptibility that hamper the conduct of successful clinical trials in ARDS and the complete absence of novel disease-modifying therapeutic strategies. The current ARDS definition relies on clinical characteristics that fail to capture the diversity of disease pathology, severity, and mortality risk. We undertook a comprehensive survey of the available ARDS literature to identify genes and genetic variants (candidate gene and limited genome-wide association study approaches) implicated in susceptibility to developing ARDS in hopes of uncovering novel biomarkers for ARDS risk and mortality and potentially novel therapeutic targets in ARDS. We further attempted to address the well-known health disparities that exist in susceptibility to and mortality from ARDS. Bioinformatic analyses identified 201 ARDS candidate genes with pathway analysis indicating a strong predominance in key evolutionarily conserved inflammatory pathways, including reactive oxygen species, innate immunity-related inflammation, and endothelial vascular signaling pathways. Future studies employing a system biology approach that combines clinical characteristics, genomics, transcriptomics, and proteomics may allow for a better definition of biologically relevant pathways and genotype-phenotype connections and result in improved strategies for the sub-phenotyping of diverse ARDS patients molecular signatures. These efforts should facilitate the potential for successful clinical trials in ARDS and yield a better fundamental understanding of ARDS pathobiology.
- Bime, C., Bime, C., Pouladi, N., Pouladi, N., Sammani, S., Sammani, S., Batai, K., Batai, K., Casanova, N., Casanova, N., Zhou, T., Zhou, T., Kempf, C., & Kempf, C. (2018). GWAS in African Americans identifies the Selectin P Ligand gene, SELPLG, as an ARDS risk gene. American J Respiratory Critical Care Medicine.
- Bime, C., Pouladi, N., Sammani, S., Batai, K., Casanova, N., Zhou, T., Kempf, C. L., Sun, X., Camp, S. M., Wang, T., Kittles, R. A., Lussier, Y. A., Jones, T. K., Reilly, J. P., Meyer, N. J., Christie, J. D., Karnes, J. H., Gonzalez-Garay, M., Christiani, D. C., , Yates, C. R., et al. (2018). Genome-Wide Association Study in African Americans with Acute Respiratory Distress Syndrome Identifies the Selectin P Ligand Gene as a Risk Factor. American journal of respiratory and critical care medicine, 197(11), 1421-1432.More infoGenetic factors are involved in acute respiratory distress syndrome (ARDS) susceptibility. Identification of novel candidate genes associated with increased risk and severity will improve our understanding of ARDS pathophysiology and enhance efforts to develop novel preventive and therapeutic approaches.
- Lynn, H. D., Sun, X., Ayshiev, D., Karnes, J. H., Gonzalez-Garay, M. L., Casanova, N., Wang, T., Garcia, J. G., & Siegler, J. H. (2018). Single nucleotide polymorphisms (SNPs) in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PLOS ONE, 13, 13(8):e0200916.
- Lynn, H. D., Sun, X., Ayshiev, D., Karnes, J. H., Gonzalez-Garay, M. L., Casanova, N., Wang, T., Garcia, J. G., & Siegler, J. H. (2018). Single nucleotide polymorphisms (SNPs) in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PLOS ONE.More infoWe previously reported that MYLKP1, the pseudogene of MYLK that encodes myosin light chain kinase (MLCK), is highly expressed in lung and colon cancer cell lines and tissues but not in normal lung or colon. The MYLKP1 promoter is minimally active in normal bronchial epithelial cells but highly active in lung adenocarcinoma cells. In this study, we further validate MYLKP1 as an oncogene via elucidation of the functional role of MYLKP1 genetic variants in colon cancer risk
- Lynn, H., Sun, X., Ayshiev, D., Siegler, J. H., Rizzo, A. N., Karnes, J. H., Gonzales Garay, M., Wang, T., Casanova, N., Camp, S. M., Ellis, N. A., & Garcia, J. G. (2018). Single nucleotide polymorphisms in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PloS one, 13(8), e0200916.More infoPseudogenes are paralogues of functional genes historically viewed as defunct due to either the lack of regulatory elements or the presence of frameshift mutations. Recent evidence, however, suggests that pseudogenes may regulate gene expression, although the functional role of pseudogenes remains largely unknown. We previously reported that MYLKP1, the pseudogene of MYLK that encodes myosin light chain kinase (MLCK), is highly expressed in lung and colon cancer cell lines and tissues but not in normal lung or colon. The MYLKP1 promoter is minimally active in normal bronchial epithelial cells but highly active in lung adenocarcinoma cells. In this study, we further validate MYLKP1 as an oncogene via elucidation of the functional role of MYLKP1 genetic variants in colon cancer risk.
- Zhou, T., Casanova, N., Pouladi, N., Wang, T., Lussier, Y., Knox, K. S., & Garcia, J. G. (2017). Identification of Jak-STAT signaling involvement in sarcoidosis severity via a novel microRNA-regulated peripheral blood mononuclear cell gene signature. Scientific reports, 7(1), 4237.More infoSarcoidosis is a granulomatous lung disorder of unknown cause. The majority of individuals with sarcoidosis spontaneously achieve full remission (uncomplicated sarcoidosis), however, ~20% of sarcoidosis-affected individuals experience progressive lung disease or cardiac and nervous system involvement (complicated sarcoidosis). We investigated peripheral blood mononuclear cell (PBMC) microRNA and protein-coding gene expression data from healthy controls and patients with uncomplicated or complicated sarcoidosis. We identified 46 microRNAs and 1,559 genes that were differentially expressed across a continuum of sarcoidosis severity (healthy control → uncomplicated sarcoidosis → complicated sarcoidosis). A total of 19 microRNA-mRNA regulatory pairs were identified within these deregulated microRNAs and mRNAs, which consisted of 17 unique protein-coding genes yielding a 17-gene signature. Pathway analysis of the 17-gene signature revealed Jak-STAT signaling pathway as the most significantly represented pathway. A severity score was assigned to each patient based on the expression of the 17-gene signature and a significant increasing trend in the severity score was observed from healthy control, to uncomplicated sarcoidosis, and finally to complicated sarcoidosis. In addition, this microRNA-regulated gene signature differentiates sarcoidosis patients from healthy controls in independent validation cohorts. Our study suggests that PBMC gene expression is useful in diagnosis of sarcoidosis.
- Singla, S., Zhou, T., Javaid, K., Abbasi, T., Casanova, N., Zhang, W., Ma, S. F., Wade, M. S., Noth, I., Sweiss, N. J., Garcia, J. G., & Machado, R. F. (2016). Expression profiling elucidates a molecular gene signature for pulmonary hypertension in sarcoidosis. Pulmonary circulation, 6(4), 465-471.More infoPulmonary hypertension (PH), when it complicates sarcoidosis, carries a poor prognosis, in part because it is difficult to detect early in patients with worsening respiratory symptoms. Pathogenesis of sarcoidosis occurs via incompletely characterized mechanisms that are distinct from the mechanisms of pulmonary vascular remodeling well known to occur in conjunction with other chronic lung diseases. To address the need for a biomarker to aid in early detection as well as the gap in knowledge regarding the mechanisms of PH in sarcoidosis, we used genome-wide peripheral blood gene expression analysis and identified an 18-gene signature capable of distinguishing sarcoidosis patients with PH (n = 8), sarcoidosis patients without PH (n = 17), and healthy controls (n = 45). The discriminative accuracy of this 18-gene signature was 100% in separating sarcoidosis patients with PH from those without it. If validated in a large replicate cohort, this signature could potentially be used as a diagnostic molecular biomarker for sarcoidosis-associated PH.
- Casanova, N., Zhou, T., Knox, K. S., & Garcia, J. G. (2015). Identifying Novel Biomarkers in Sarcoidosis Using Genome-Based Approaches. Clinics in chest medicine, 36(4), 621-30.More infoThis article briefly reviews conventional biomarkers used clinically to (1) support a diagnosis and (2) monitor disease progression in patients with sarcoidosis. Potential new biomarkers identified by genome-wide screening and the approaches to discover these biomarkers are described.
- Moller, D. R., Koth, L. L., Maier, L. A., Morris, A., Drake, W., Rossman, M., Leader, J. K., Collman, R. G., Hamzeh, N., Sweiss, N. J., Zhang, Y., O'Neal, S., Senior, R. M., Becich, M., Hochheiser, H. S., Kaminski, N., Wisniewski, S. R., Gibson, K. F., & , G. S. (2015). Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) Study. Sarcoidosis Protocol. Annals of the American Thoracic Society, 12(10), 1561-71.More infoSarcoidosis is a systemic disease characterized by noncaseating granulomatous inflammation with tremendous clinical heterogeneity and uncertain pathobiology and lacking in clinically useful biomarkers. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study is an observational cohort study designed to explore the role of the lung microbiome and genome in these two diseases. This article describes the design and rationale for the GRADS study sarcoidosis protocol. The study addresses the hypothesis that distinct patterns in the lung microbiome are characteristic of sarcoidosis phenotypes and are reflected in changes in systemic inflammatory responses as measured by peripheral blood changes in gene transcription. The goal is to enroll 400 participants, with a minimum of 35 in each of 9 clinical phenotype subgroups prioritized by their clinical relevance to understanding of the pathobiology and clinical heterogeneity of sarcoidosis. Participants with a confirmed diagnosis of sarcoidosis undergo a baseline visit with self-administered questionnaires, chest computed tomography, pulmonary function tests, and blood and urine testing. A research or clinical bronchoscopy with a research bronchoalveolar lavage will be performed to obtain samples for genomic and microbiome analyses. Comparisons will be made by blood genomic analysis and with clinical phenotypic variables. A 6-month follow-up visit is planned to assess each participant's clinical course. By the use of an integrative approach to the analysis of the microbiome and genome in selected clinical phenotypes, the GRADS study is powerfully positioned to inform and direct studies on the pathobiology of sarcoidosis, identify diagnostic or prognostic biomarkers, and provide novel molecular phenotypes that could lead to improved personalized approaches to therapy for sarcoidosis.
- Strange, C., Senior, R. M., Sciurba, F., O'Neal, S., Morris, A., Wisniewski, S. R., Bowler, R., Hochheiser, H. S., Becich, M. J., Zhang, Y., Leader, J. K., Methé, B. A., Kaminski, N., Sandhaus, R. A., & , G. A. (2015). Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol. Annals of the American Thoracic Society, 12(10), 1551-60.More infoSevere deficiency of alpha-1 antitrypsin has a highly variable clinical presentation. The Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis α1 Study is a prospective, multicenter, cross-sectional study of adults older than age 35 years with PiZZ or PiMZ alpha-1 antitrypsin genotypes. It is designed to better understand if microbial factors influence this heterogeneity. Clinical symptoms, pulmonary function testing, computed chest tomography, exercise capacity, and bronchoalveolar lavage (BAL) will be used to define chronic obstructive pulmonary disease (COPD) phenotypes that can be studied with an integrated systems biology approach that includes plasma proteomics; mouth, BAL, and stool microbiome and virome analysis; and blood microRNA and blood mononuclear cell RNA and DNA profiling. We will rely on global genome, transcriptome, proteome, and metabolome datasets. Matched cohorts of PiZZ participants on or off alpha-1 antitrypsin augmentation therapy, PiMZ participants not on augmentation therapy, and control participants from the Subpopulations and Intermediate Outcome Measures in COPD Study who match on FEV1 and age will be compared. In the primary analysis, we will determine if the PiZZ individuals on augmentation therapy have a difference in lower respiratory tract microbes identified compared with matched PiZZ individuals who are not on augmentation therapy. By characterizing the microbiome in alpha-1 antitrypsin deficiency (AATD), we hope to define new phenotypes of COPD that explain some of the diversity of clinical presentations. As a unique genetic cause of COPD, AATD may inform typical COPD pathogenesis, and better understanding of it may illuminate the complex interplay between environment and genetics. Although the biologic approaches are hypothesis generating, the results may lead to development of novel biomarkers, better understanding of COPD phenotypes, and development of novel diagnostic and therapeutic trials in AATD and COPD. Clinical trial registered with www.clinicaltrials.gov (NCT01832220).
- Zhang, X., Zhang, W., Ma, S. F., Desai, A. A., Saraf, S., Miasniakova, G., Sergueeva, A., Ammosova, T., Xu, M., Nekhai, S., Abbasi, T., Casanova, N. G., Steinberg, M. H., Baldwin, C. T., Sebastiani, P., Prchal, J. T., Kittles, R., Garcia, J. G., Machado, R. F., & Gordeuk, V. R. (2014). Hypoxic response contributes to altered gene expression and precapillary pulmonary hypertension in patients with sickle cell disease. Circulation, 129(16), 1650-8.More infoWe postulated that the hypoxic response in sickle cell disease (SCD) contributes to altered gene expression and pulmonary hypertension, a complication associated with early mortality.
- Casanova, N., Casanova, N., Gonzalez-Garay, M. L., Gonzalez-Garay, M. L., Sun, B., Sun, B., Sun, X., Sun, X., Garcia, J. G., & Garcia, J. G. (2019, May). Sarcoidosis And Coccidioidomycosis Share Common Tissue Transcriptome Expression Profiles. ATS International Conference. Dallas: American Thoracic Society.More infoIn this study we compared sarcoidosis gene expression profiles of lung and lymph node granulomas to tissues from patients with tuberculosis and coccidioidomycosis or Valley Fever (VF), a soil-dwelling fungi disease endemic in the southwest. We also aimed to compare sarcoidosis tissue gene expression to our previous gene signatures derived from peripheral blood mononuclear (PBMC). Incorporation of precise approaches like molecular biomarkers in the differential diagnosis will facilitate and expedite the diagnosis.
- Berghout, J., Lussier, Y. A., Navarrete, J., Garcia, J. G., Knox, K. S., Pouladi, N., Gonzalez-Garay, M. L., & Casanova, N. (2017, May). TNF-α specific PBMC responses in complicated and uncomplicated sarcoidosis by RNA-Seq. American Thoracic Society International Conference. Washington DC: ATS.
- Casanova, N., Berghout, J., Gonzalez-Garay, M. L., Lussier, Y. A., Pouladi, N., Navarrete, J., Knox, K. S., Garcia, J. G., Garcia, J. G., Knox, K. S., Pouladi, N., Navarrete, J., Lussier, Y. A., Gonzalez-Garay, M. L., Berghout, J., & Casanova, N. (2017, May). TNF-α specific PBMC responses in complicated and uncomplicated sarcoidosis by RNA-Seq. American Thoracic Society International Conference. Washington DC: ATS.
- Casanova, N., Gonzalez-Garay, M. L., Knox, K. S., & Garcia, J. G. (2017, April). Identifying responsive TNF-α transcripts in complicated Sarcoidosis. PRIDE Annual Meeting. Bethesda, MD: NIH.More infoPrograms to Increase Diversity Among Individuals Engaged in Health-Related Research (PRIDE).
- Casanova, N., Zhou, T., Knox, K. S., & Garcia, J. G. (2016, May). Peripheral Blood MicroRNA Signature Differentiates Sarcoidosis. American Thoracic Society International Conference. San Francisco: ATS.