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Faculty Profile Last Modified Time: 02:13:41 PM Fri, 17 Apr 2020   Contact Information John Wilson Associated Profiles  Distinguished Service Professor, Biochemistry & Molecular Biology, and Molecular & Human Genetics, Baylor College of Medicine   Mail Box: BCM125, BCM-Ben Taub Research Center, Room No.: BCMT-T342    jwilson@bcm.edu     713-798-5760    Web Link    Mouse and Rat, Neural Plasticity and Degeneration, Gene Therapy, Chromosomes, Chromatin, DNA Biology, Development and Evolution, Molecular Basis of Human Disease and Behavior    Associated Profiles Research and Expertise Affiliations Appointments  Research and Expertise Research Interests   We are interested in two, complementary aspects of genome biology: defining the pathways that control the stability of disease-causing trinucleotide repeats, and developing methods to accomplish precise gene modifications for gene therapy. We are exploring these interests in the context of inherited human neurological diseases. Instability of Trinucleotide Repeats: Expansions of trinucleotide repeats in specific human genes cause several neurodegenerative diseases such as Huntington disease and myotonic dystrophy. The basis for repeat instability—their ability to expand and contract the number of repeats in a tract—is unclear. To define these mechanisms, we have developed exquisitely sensitive assays that detect repeat instability in mammalian cells. These assays reveal that CAG repeats are dramatically destabilized by transcription through the repeat, by genome-wide demethylation, and by environmental stresses such as hypoxia, heat shock, cold shock, and oxidative stress. By knocking down expression of specific genes in human cells with siRNAs, and using gene mutations in mice, we are identifying the roles of various genes and DNA metabolic processes that are responsible for repeat instability. In addition, we are optimizing the use of zinc-finger nucleases that introduce double-strand breaks into CAG repeats, and zinc-finger nickases that introduce single strand breaks, as reagents to shrink long CAG tracts as a potential therapy for human patients. Targeted Genome Modification: Retinitis pigmentosa (RP), which affects 1 in every 3000 people worldwide, typically begins with loss of peripheral vision in the teens and progresses to tunnel vision and blindness in middle age. We are developing gene-specific strategies for genome modification, with the ultimate aim of treating this disease in humans. Dominant mutations in the rhodopsin gene are the largest single cause of RP. To develop treatment protocols, we have generated mouse models in which one copy of the mouse rhodopsin gene is replaced with one or another forms of the human rhodopsin gene fused to GFP. These fluorescently tagged mouse models provide convenient color markers for the assessment of treatment efficacy. We are using these mouse models to test and optimize various gene specific cleavage reagents such as zinc-finger nucleases for their ability to correct or knockout defective genes. These studies will also elucidate the DNA repair capabilities of terminally differentiated neurons, which are currently undefined.  Publications/Creative Works Click here to search for this faculty member's publications on PubMed.  Affiliations  Research Consortia John S. Dunn GCC for Chemical Genomics  Appointments Title Department / School Institution Distinguished Service Professor Biochemistry & Molecular Biology, Molecular & Human Genetics Baylor College of Medicine

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