Joe GN Garcia
Professor, BIO5 Institute
Professor, Internal Medicine
Professor, Medicine
Professor, Pharmacology and Toxicology
Professor, Physiological Sciences - GIDP
Professor, Physiology
Primary Department
Department Affiliations
(520) 626-3151
Work Summary
The Garcia laboratory works to understand the molecular mechanisms of lung inflammatory processes, particularly those producing lung edema or vascular leak. The laboratory focus is to investigate gene discovery, protein function assessment, SNP discovery, genetic manipulation, in vivo testing, and candidate gene and biomarker identification, working to translate basic research into potential novel clinical therapies.
Research Interest
Dr. Garcia is an authority on the genetic basis of inflammatory lung disease (with an emphasis on health disparities) and on the mechanistic basis of lung vascular permeability. Using bench-to-bedside approaches, his lab has explored novel methods to prevent vascular leak and to restore endothelial cell barrier function and vascular integrity. This expertise in lung inflammation and vascular permeability provides a natural linkage to interrogation of lung vascular contribution to the development of lung metastases. Leveraging their genomic expertise, in recent years, Dr. Garcia's lab has identified vascular genes whose products are key participants in inflammatory lung injury that also play a role in cancer development. They have developed lung endothelial inflammatory gene expression profiles as well as diagnostic gene signatures influenced by MYLK and NAMPT that impact lung and breast cancer prognosis. This work with NAMPT led to development of a therapeutic NAMPT neutralizing antibody that has shown promise in treating lung cancer, melanoma, and chronic lymphocytic leukemia. Finally, Dr. Garcia's lab is also interested in the untoward effect of thoracic radiation and has been examining strategies designed to attenuate radiation–induced pneumonits, fibrosis and vascular leak. These collaborative and highly translational cancer research efforts have bolstered the overall mission of the University of Arizona Cancer Center.

Publications

Sun, X., Mathew, B., Sammani, S., Jacobson, J. R., & Garcia, J. G. (2016). Simvastatin- Induced Sphingosine 1−Phosphate Receptor 1 Expression is KLF2-Dependent in Human Lung Endothelial Cells. Pulmonary Circulation.
Siegler, J. H., Siegler, J. H., Garcia, J. G., Garcia, J. G., Wang, T., Wang, T., Casanova, N., Casanova, N., Gonzalez-Garay, M. L., Gonzalez-Garay, M. L., Karnes, J. H., Karnes, J. H., Ayshiev, D., Ayshiev, D., Sun, X., Sun, X., Lynn, H. D., & Lynn, H. D. (2018). Single nucleotide polymorphisms (SNPs) in the MYLKP1 pseudogene are associated with increased colon cancer risk in African Americans. PLOS ONE.
Desai, A., Black, S., Wang, T., Garcia, J. G., Sun, X., Adyshev, D., Kelly, G. T., Camp, S. M., & Elangovan, V. R. (2016). Endotoxin- and mechanical stress-induced epigenetic changes in the regulation of the nicotinamide phosphoribosyltransferase promoter. Pulmonary circulation, 6(4), 539-544.

Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator-induced lung injury (VILI) is not well characterized. On the basis of an emerging role for epigenetics in enrichment of VILI and CpG sites within the NAMPT promoter and 5'UTR, we hypothesized that NAMPT expression and downstream transcriptional events are influenced by epigenetic mechanisms. Concomitantly, excessive mechanical stress of human pulmonary artery endothelial cells or lipopolysaccharide (LPS) treatment led to both reduced DNA methylation levels in the NAMPT promoter and increased gene transcription. Histone deacetylase inhibition by trichostatin A or Sirt-1-silencing RNA attenuates LPS-induced NAMPT expression. Furthermore, recombinant NAMPT administration induced TLR4-dependent global H3K9 hypoacetylation. These studies suggest a complex epigenetic regulatory network of NAMPT in VILI and ARDS and open novel strategies for combating VILI and ARDS.

Black, S., Yuan, J., Garcia, A. N., Jacobson, J. R., Garcia, J. G., Wu, X., Zemskov, E., Desai, A., Gross, C., & Wang, T. (2017). Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets. American journal of physiology. Lung cellular and molecular physiology, 312(4), L452-L476.

Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS shares many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell barrier integrity resulting in alveolar flooding. While there have been advances in the understanding of certain elements of VILI and ARDS pathobiology, such as defining the importance of lung inflammatory leukocyte infiltration and highly induced cytokine expression, a deep understanding of the initiating and regulatory pathways involved in these inflammatory responses remains poorly understood. Prevailing evidence indicates that loss of endothelial barrier function plays a primary role in the development of VILI and ARDS. Thus this review will focus on the latest knowledge related to 1) the key role of the endothelium in the pathogenesis of VILI; 2) the transcription factors that relay the effects of excessive mechanical stress in the endothelium; 3) the mechanical stress-induced posttranslational modifications that influence key signaling pathways involved in VILI responses in the endothelium; 4) the genetic and epigenetic regulation of key target genes in the endothelium that are involved in VILI responses; and 5) the need for novel therapeutic strategies for VILI that can preserve endothelial barrier function.

Yuan, J., Makino, A., Garcia, J. G., Khalpey, Z. I., Black, S., Wang, J., Rischard, F., Desai, A., Cordery, A. G., Wang, Z., Dash, S., Sun, X., Zhou, T., Gupta, A., Song, S., Ayon, R. J., Gu, Y., McDermott, K. M., Babicheva, A., & Tang, H. (2017). Endothelial HIF-2α contributes to the development of severe pulmonary hypertension by inducing endothelial-to-mesenchymal transition. American J Physiology Lung Cellular Molecular Physiology..