Human and viral genes are complex units of information whose tightly regulated expression produces a dazzling array of phenotypes. The Garcia-Blanco laboratory focuses on gene expression from the perspective of RNA biology. The laboratory studies gene expression in two biological contexts of biomedical importance: Infection of human and insect cells with flaviviruses such as dengue and yellow fever viruses, and autoimmune diseases such as multiple sclerosis.
1. Human and insect host factors important for flaviviruses.
Flaviviruses are a major health problem in the tropics and represent an emerging danger to global health. This threat was loudly announced by the North American West Nile virus epidemic, and recent Dengue outbreaks in France and the US. Comparatively little is known about the molecular biology of these viruses, and the Garcia-Blanco laboratory is identifying host factors, both insect and human, that impact on the infection with pathogenic flaviviruses using en masse approaches. Some of these factors, dependency factors, are required for efficient viral replication, while others, restriction factors, are components limit infectivity and are part of the host innate defense against viral pathogens. Given that flaviviruses live in an RNA world, never using DNA as genetic material, many of the newly identified host factors are RNA binding proteins. The work on flaviviruses is carried out at UTMB in collaboration with my co-Principal Investigator Dr. Shelton Bradrick, and at the Duke-NUS Graduate Medical School in Singapore.
2. Alternative splicing in autoimmunity.
In collaboration with Dr. Simon Gregory (Duke University), we showed that a SNP associated with increased risk of multiple sclerosis was important in the regulation of the alternative splicing of IL-7 receptor alpha subunit transcripts. This receptor is critical for Tcell ontogeny and function, which are intimately linked to the development of multiple sclerosis. The alternative splicing affected by the SNP determines the ratio of soluble vs membrane bound receptor in Tcells by differential inclusion of exon 6. We have characterized the cis-elements and trans-acting factors that regulate inclusion of this exon. Recently we have focused our studies on the RNA DEAD-box helicase DDX39B, which activates inclusion of IL7R exon 6 reducing multiple sclerosis risk. This alternative splicing regulator likely plays an important role in autoimmunity and inflammation. These studies should provide further insights into understudied autoimmune disorders.
Mariano A. Garcia-Blanco MD, PhD, is Professor and Chair of Biochemistry and Molecular Biology at the University of Texas Medical Branch in Galveston TX, USA, where he is also Mildred Hajek Vacek and John Roman Vacek Distinguished Chair in Honor of President Truman G. Blocker, Jr. He is also Professor of Emerging Infectious Diseases at the Duke-NUS Graduate Medical School in Singapore. Professor Garcia-Blanco obtained his AB in Biochemical Sciences at Harvard College, and his MD and PhD (in Molecular Biophysics and Biochemistry) at Yale University. He obtained postdoctoral training in RNA biology with Nobel laureate Phillip A. Sharp at MIT. From 1990 to 2014 he was at Duke University where he was the Charles D. Watts Professor of Molecular Genetics and Microbiology, and Medicine, and Director of the Center for RNA Biology at Duke University in the USA. Professor Garcia-Blanco is an internationally recognized expert in RNA biology and is an author of more than 130 scientific publications. Additionally, he co-founded Intronn Inc. (now VIRxSYS, Rockville, MD, USA) to develop a novel trans-splicing RNA therapy, and Veri-Q Inc. (part of Proteome Sciences plc, Cobham, UK), to commercialize reagents for the quality control of chemically synthesized nucleic acids, and more recently Singapore Advanced Biologics Pte Ltd (SABio). Professor Garcia-Blanco has served as a member of Scientific Advisory Board for European Alternative Splicing Network of Excellence (EU), National Advisory General Medical Sciences Council (NIH, USA), and of the Puerto Rico Trust for Science, Research and Technology. He is currently a member of the Council of Scientific Advisers for the International Centre for Genetic Engineering and Biotechnology (United Nations). In 2011 he was elected to the Association of American Physicians (AAP), in 2012 fellow of the American Association for the Advancement of Science, and in 2013 fellow of the American Academy of Microbiology.