Photo of Joe GN Garcia
Joe GN Garcia
Professor, BIO5 Institute
Professor, Internal Medicine
Professor, Medicine
Professor, Pharmacology and Toxicology
Professor, Physiological Sciences - GIDP
Professor, Physiology
Primary Department
Medicine
Department Affiliations
Senior VP Health Sciences
Medicine
(520) 626-3151
skipgarcia@email.arizona.edu
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

Champion, H. C., Champion, H. C., Vanderpool, R., Vanderpool, R., Garcia, J. G., Garcia, J. G., Yuan, J., Yuan, J., Abidov, A., Abidov, A., Desai, A., Desai, A., Knapp, S. M., Knapp, S. M., Knoper, S. R., Knoper, S. R., Hansen, L., Hansen, L., Simon, M., , Simon, M., et al. (2017). Treprostinil decreases right ventricular contractility but improves ejection fraction and exercise capacity in pulmonary arterial hypertension. European Respiratory J.
Singleton, P. A., Mambetsariev, N., Lennon, F. E., Mathew, B., Siegler, J. H., Moreno-Vinasco, L., Salgia, R., Moss, J., & Garcia, J. G. (2010). Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors. Journal of angiogenesis research, 2(1), 5.

Recent cancer therapies include drugs that target both tumor growth and angiogenesis including mammalian target of rapamycin (mTOR) inhibitors. Since mTOR inhibitor therapy is associated with significant side effects, we examined potential agents that can reduce the therapeutic dose.

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.