A. Javier Lopez
Associate Professor of Biological Sciences
ResearchExpression of almost all genes in humans and other animals requires splicing of pre-mRNAs during or after their transcription from DNA. Splicing involves removing and discarding portions of the transcript (“introns”) and re-joining the remaining portions (“exons”), which are retained for use as mRNAs to encode proteins. Multiple patterns of intron and exon definition can exist for transcripts from a given gene, a phenomenon known as alternative splicing. This results in the ability to encode multiple structurally and functionally distinct mRNAs (and their corresponding proteins) from a given gene. Alternative splicing is a widespread regulatory strategy that impacts development, adaptation and disease susceptibility. The focus of my research is to understand the mechanisms that regulate alternative splicing and its functional consequences in the context of development, aging, and disease. We use genetic, genomic, molecular and computational approaches. Our primary model system is Drosophila, the laboratory fruitfly, but we also work with insect and mammalian cell lines and have collaborated recently with human geneticists to investigate the role of alternative splicing variation as a genetic risk factor for schizophrenia.
Currently, the Lopez lab is working on two projects in Drosophila that are linked by the context of aging. The first project investigates mechanisms of alternative splicing and subcellular localization of mRNAs for muscle proteins and how these change with age. These studies should contribute to a better understanding of mechanisms that underlie reduction in muscle function during aging as well as muscle degeneration in human diseases such as myotonic dystrophies in which processing of such mRNAs is disturbed. The second project investigates the regulatory pathways and mechanisms that control aging-associated changes in alternative splicing of mRNAs involved in energy metabolism, generation of reactive oxygen species, and response to oxidative stress. These processes play important roles in aging, cancer and neurodegenerative diseases. Recently, a large number of aging-associated changes in alternative splicing have been identified in human brain, and we have identified hundreds of such changes in multiple tissues of Drosophila. For selected genes, we have also found that similar changes are produced in response to oxidative stress. In Drosophila, we have the ability to perform detailed studies of the regulation and functional consequences of such changes during normal aging time courses and in genetically uniform lines with lifespans that are extended or shortened by genetic manipulations or environmental effects. In both projects we collaborate with Dr. Bruce Armitage to develop novel probe technologies for analysis of subcellular RNA localization and quantitation of alternative splicing in individual cells within whole animals.
Nimgaonkar, VL; Chowdari, KV; Prasad, KM; Watson, A; Mansour, H; Wood, J.A.; Lopez, A.J. What can be learned from nominally significant/discrepant associations? An illustration using dopamine gene variants and schizophrenia. in Schizophrenia: The Final Frontier; David, A.S.; Kapur, S; McGuffin, P, Eds.; Taylor and Francis Ltd., 2011, ISBN-13: 978-1848720770.
Talkowski, M.E.; McCann, K.L.; Chen, M. Y-M; McClain, L; Bamne, M; Wood, J; Chowdari, K.V.; Kirov, G.; Georgieva, L.; Toncheva, D.; Mansour, H.; Lewis, D.A.; Owen, M.; O’Donovan, M.; Papasaikas, P.; Sullivan, P.; Sklar, P.; Ruderfer, D. and ISC consortium, Yao, JK; Leonard, S.; Thomas, P; Miyajima, F.; Quinn, J.; Lopez, A.J.; Nimgaonkar, V.L. Fine mapping reveals novel alternative splicing of the dopamine transporter. Am J Med Genet B Neuropsychiatr Genet 2010, 153B(8):1434-1447
Robertson, K.L.; Yu, L.; Armitage, B.A.; Lopez, A.J., Peteanu, L.A. Fluorescent PNA probes as hybridization labels for biological RNA. Biochemistry 2006, 45:6066-6074
Burnette, J.M.; Miyamoto-Sato, E.; Schaub, M.A.; Conklin, J.; Lopez, A.J. Subdivision of large introns in Drosophila by recursive splicing at non-exonic elements. Genetics 2005, 170: 661-674
Conklin, J.; Goldman, A.; Lopez, A.J. Stabilization and analysis of intron lariats in vivo. Methods 2005. 37: 368-375
Kumar, S.; Lopez, A.J. Negative feedback regulation among SR splicing factors encoded by Rbp1 and Rbp1-like in Drosophila. EMBO J 2005, 24: 2646-2655