个人简介
Kivie Moldave Graduate Student Award, Department of Biological Chemistry (1988), Hereditary Disease Foundation Postdoctoral Fellowship (1989-90), National Medical Research Award of the National Health Council (1993), Kaiser-Permanente Excellence in Teaching (1996), Hereditary Disease Foundation
Lieberman Award (1997-1999), UCI College of Medicine, Health Science Partners (1999), UCI College of Medicine, AMWA Gender Equity Award (1999), UCI College of Medicine, Silver Beaker award to the Outstanding Basic Science Faculty Member (1999), Hereditary Disease Foundation Scientific Advisory Board (2000-2007), Huntington's Disease Society of America Coalition for the Cure Investigator (2001-present), Distinguished Assistant Professor Award for Research, UC Irvine (2002), Huntington’s Disease Society of America Distinguished Leadership Award (2002), UCI College of Medicine, Excellence in Teaching (2004, 2005, 2006, 2007), 2006 Office of Educational Affairs MVP Outstanding Service Award, 2006-present standing member CMND NIH study section, 2005-present F1000 Neurological Disorders Faculty, 2007 Fellow, Center for Learning and Memory.
研究领域
Discoveries in human genetics have allowed investigators to make significant progress in understanding the underlying cellular mechanisms that are disrupted by these mutations and to develop rational therapeutics. The research in the Thompson lab has largely focused on understanding pathogenic mechanisms for neurodegenerative disease and FGFR3-associated cancers in order to identify and validate novel therapeutic targets for treatment of these diseases.
HD is an autosomal dominant neurodegenerative disease characterized by specific regions of neuronal dysfunction and loss, most notably of neurons in the striatum and cortex. There is currently no effective treatment or cure for this devastating disorder. The primary cause of HD is the expansion of a CAG triplet repeat encoding a polyglutamine (polyQ) tract within the amino terminal portion of a predominantly extranuclear protein, Huntingtin (Htt). Work from our lab and others suggest that this mutation disrupts many cellular processes, including transcriptional regulation, vesicular trafficking, mitochondrial function, degradation pathways, protein modification, protein folding and processing pathways. Protein aggregates and inclusions in affected brain regions, presumably the consequence of abnormal protein folding and/or proteolytic cleavage and degradation of the polyQ repeat-containing protein, are common hallmarks in all polyQ disorders. Cleavage of full-length Htt appears to be an important step in pathogenesis, as does subsequent nuclear accumulation of mutant Htt. Understanding the molecular basis of neuronal dysfunction and death as a consequence of CAG repeat expansion, which appears to confer a dominant toxicity, is critical to development of effective therapies.
The molecular and cellular basis of HD pathogenesis is studied using multidisciplinary systems including in vitro, cell culture, Drosophila and mouse models. In collaboration with Dr. J. Lawrence Marsh at UCI, a Drosophila model to study triplet repeat pathogenesis is effective at modeling disease pathogenesis and is part of a long standing collaboration between the two labs. Approaches to investigate neuronal dysfunction include targeted studies of Htt oligomerization and its role in neurotoxicity, transcriptional dysregulation in the context of chromatin remodeling and epigenetics, protein modifications of the mutant protein that influences its clearance and cellular localization, and altered signal transduction in HD. Together with Dr. Joan Steffan at UCI, we are focusing upon the role of post-translational modifications of the Htt protein in cellular localization, transcription and protein clearance. Genetic and pharmacologic approaches to develop therapeutics are active areas of research using each of these systems. However, since molecular commonalities such as defective signal transduction, aggregation and altered transcription have emerged for diseases that involve aberrant protein folding such as Alzheimer’s disease, these efforts have applications to a wide range of neurodegenerative diseases.
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Lee JH, Tecedor L, Chen YH, Monteys AM, Sowada MJ, Thompson LM, Davidson BL. (2015). Reinstating aberrant mTORC1 activity in Huntington's disease mice improves disease phenotypes. Neuron. Jan 21;85(2):303-15. PMID: 25556834
Miller S, Hill Della Puppa G, Reidling J, Marcora E, Thompson LM, Treanor J. (2014). Comparison of phosphodiesterase 10A, dopamine receptors D1 and D2 and dopamine transporter ligand binding in the striatum of the R6/2 and BACHD mouse models of Huntington's disease. J Huntingtons Dis.;3(4):333-41. PMID: 25575954
Liu KY, Shyu YC, Barbaro BA, Lin YT, Chern Y, Thompson LM, James Shen CK, Marsh JL. (2015). Disruption of the nuclear membrane by perinuclear inclusions of mutant huntingtin causes cell-cycle re-entry and striatal cell death in mouse and cell models of Huntington's disease. Hum Mol Genet. Mar 15;24(6):1602-16. PMID: 25398943
Ochaba J, Lukacsovich T, Csikos G, Zheng S, Margulis J, Salazar L, Mao K, Lau AL, Yeung SY, Humbert S, Saudou F, Klionsky DJ, Finkbeiner S, Zeitlin SO, Marsh JL, Housman DE, Thompson LM, Steffan JS (2014). Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A. Nov 25;111(47):16889-94. PMID: 25385587
Salazar L, Kashiwada T, Krejci P, Meyer AN, Casale M, Hallowell M, Wilcox WR, Donoghue DJ, Thompson LM (2014). Fibroblast growth factor receptor 3 interacts with and activates TGFß-activated kinase 1 tyrosine phosphorylation and NF?B signaling in multiple myeloma and bladder cancer. PLoS One. Jan 23;9(1):e86470. PMID: 24466111
Mattis VB, Wakeman DR, Tom C, Dodiya HB, Yeung SY, Tran AH, Bernau K, Ornelas L, Sahabian A, Reidling J, Sareen D, Thompson LM, Kordower JH, Svendsen CN (2014). Neonatal immune-tolerance in mice does not prevent xenograft rejection. Exp Neurol. Apr;254:90-8. PMID: 24440640
Vashishtha M, Ng CW, Yildirim F, Gipson TA, Kratter IH, Bodai L, Song W, Lau A, Labadorf A, Vogel-Ciernia A, Troncosco J, Ross CA, Bates GP, Krainc D, Sadri-Vakili G, Finkbeiner S, Marsh JL, Housman DE, Fraenkel E, Thompson LM (2013). Targeting H3K4 trimethylation in Huntington disease. Proc Natl Acad Sci U S A. Aug 6;110(32):E3027-36. PMID: 23872847
O'Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, Lee J, Monteys AM, Pallos J, Mee L, Vashishtha M, Apostol BL, Nicholson TP, Illes K, Zhu YZ, Dasso M, Bates GP, Difiglia M, Davidson B, Wanker EE, Marsh JL, Lima CD, Steffan JS, Thompson LM (2013). SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. Jul 25;4(2):362-75. PMID: 23871671
Sontag EM, Joachimiak LA, Tan Z, Tomlinson A, Housman DE, Glabe CG, Potkin SG, Frydman J, Thompson LM (2013). Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes. Proc Natl Acad Sci U S A. Feb 19;110(8):3077-82. PMID: 23365139
Sontag EM, Lotz GP, Agrawal N, Tran A, Aron R, Yang G, Necula M, Lau A, Finkbeiner S, Glabe C, Marsh JL, Muchowski PJ, Thompson LM (2012). Methylene blue modulates huntingtin aggregation intermediates and is protective in Huntington's disease models. J Neurosci. Aug 8;32(32):11109-19. PMID: 22875942
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