Ph.D. University of California, Davis
M.S. Cornell University, 1991
B.A. Cornell University, 1987
My research is committed to studying the complexity inherent in biological systems for the purpose of improving human health. My lab focus is on genetic neurological and muscular degenerative diseases. I feel that model organisms are vital tools with which we can answer fundamental questions about biology and medicine, based in molecular genetics, cellular and organismal biology, and developmental/degenerative biology. My research broadly encompasses three areas with related research questions, as follows:
Theme #1: Discovery of and Functional Characterization of Genetic Modifiers of Amyotrophic Lateral Sclerosis (ALS). Within families carrying the same genetic mutations resulting in ALS, there is great variation in the age of onset and severity of the disease.
• What are the genetic modifiers that influence this variation?
• How can we use animal models to discover and test modifiers of this disease?
We have identified a strong quantitative trait locus (QTL) in mice that significantly impact the longevity of the ALS disease process, containing 34 potential modifier genes. We are investigating the impact of each of these genes for their effect on ALS phenotypes in ALS-zebrafish and motor neurons derived from embryonic stem-cells from our ALS mouse model.
Theme #2: Impact of environmental toxicants on ALS phenotypes. We know that a range of environmental neurotoxins can cause both acute and chronic neurological defects.
• Do these also interact with the molecular pathways involved in genetic forms of ALS?
My lab is investigating whether the motor neuron defects seen in zebrafish models of ALS are exacerbated by early embryonic exposure to water-borne environmental toxicants. Our hope is to determine biochemical pathways that intersect between the genetic and chemical insults to discover more about commonalities between these neurological disorders.
Theme #3: Mitochondrial and Nuclear Alterations in a Novel Human Muscular Dystrophy Caused By Defects in Phospholipid Synthesis. We have identified both a mouse model and human populations with muscular dystrophy caused by changes in membrane phospholipid synthesis.
• How do changes in this enzymatic pathway result in muscle degeneration?
• What causes the severe changes in mitochondrial morphology and nuclear envelope structure?
• How are these pathways related to other mitochondrial and muscular diseases?
The mutant mouse and the human patients all exhibit the development of giant mitochondria. The fusion of muscle mitochondria into these megamitochondria may be driven by the alterations in the membrane phospholipid phosphatidylcholine, the product of the Chkb pathway. To test how megamitochondria form we can turn off the biosynthesis of phosphatidylcholine in a muscle-specific manner by the administration of tamoxifen to a genetically-manipulated mouse muscle cell culture, and we will measure the mitochondrial morphology changes that occur during membrane phospholipid perturbation, using live FPALM microscopy (with Dr. Sam Hess, Umaine).
• Sher RB, Cox GA, Ackert-Bicknell C. 2012. Development and Disease of Mouse Muscular and Skeletal Systems. In “The Laboratory Mouse, Second Edition.” (HJ Hedrich. Ed.). Elsevier Inc., San Diego.
• Sher, RB, Cox GA, Mills KD, Sundberg JP. 2011. Rhabdomyosarcomas in aging A/J mice. PLoS One. 6(8): e23498. Sher 2011 PLoS One
• Mitsuhashi S, Hatakeyama H, Karahashi M, Koumura T, Nonaka I, Hayashi YK, Noguchi S, Sher RB, Nakagawa Y, Manfredi G, Goto Y, Cox GA, Nishino I. 2011. Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy. Human Molecular Genetics 20(19): 3841-3851. Mitsuhashi 2011 Hum Mol Genet
• Mitsuhashi S, Ohkuma A, Talim B, Karahashi M, Koumura T, Aoyama C, Kurihara M, Qunlivan R, Sewry C, Mitsuhashi H, Goto K, Koksai B, Kale G, Ikeda K, Taguchi R, Noguchi S, Hayashi YK, Nonaka I, Sher RB, Sugimoto H, Nakagawa Y, Cox GA, Topaloglu H, Nishino I. 2011. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. American Journal of Human Genetics. 12(2): 79-86. Mitsuhashi 2011 Am J Hum Genet
• Heimann-Patterson TD, Sher RB, Blankenhorn EA, Alexander G, Deitch JS, Kunst CB, Maragakis N, Cox G. 2011. Effect of Genetic Background on Phenotype Variability in Transgenic Mouse Models of Amyotrophic Lateral Sclerosis: A window of opportunity in the search for genetic modifiers. Amyotrophic Lateral Sclerosis 12(2): 79-86. Heiman-Patterson ALS 2011
• Wu G, Sher RB, Cox GA, Vance DE. 2010. Differential expression of choline kinase isoforms in skeletal muscle explains the phenotypic variability in the rostrocaudal muscular dystrophy mouse. Biochim Biophys Acta. 1801(4): 446-454. Wu 2010 Biochim Biophys Acta
• Wu G, Sher RB, Cox GA, Vance DE. 2009. Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice. Biochim Biophys Acta. 1791(5): 347-356. Wu 2009 Biochim Biophys Acta
• Sher RB, Aoyama C, Huebsch KA, Ji S, Kerner J, Yang Y, Frankel WN, Hoppel CL, Wood PA, Vance DE, Cox GA. 2006. A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. Journal of Biological Chemistry 281(8): 4938-4948. Sher 2006 J Biol Chem
• Huebsch KA, Kudryashova E, Wooley CM, Sher RB, Seburn KL, Spencer MJ, Cox GA. 2005. Mdm muscular dystrophy: interactions with calpain 3 and a novel functional role for titin’s n2a domain. Human Molecular Genetics 14(19): 2801-2811. Huebsch 2005 Hum Mol Genet
• Wooley CM, Sher RB, Frankel WN, Cox GA, and Seaburn KL. 2005. Gait analysis detects early changes in transgenic SOD1(G93A) mice. Muscle Nerve 32: 43-50. Wooley 2005 Muscle Nerve
Image Description: Roger Headshot