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Roger B Sher, PhD


 

Research Associate Professor

roger.sher@stonybrook.edu

Centers for Molecular Medicine
Office: CMM 546
Lab: CMM 550/573

Office Phone: (631) 632-9664
Fax: (631) 632-6661


Research Interests/Expertise

My research is committed to studying the complexity inherent in biological systems for the purpose of improving human health.  My lab focus is on Amyotrophic Lateral Sclerosis and neurodegenerative 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 genetics and environmental toxicants on ALS phenotypes. We know that a range of environmental neurotoxins can cause both acute and chronic neurological defects.

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.

  • Do these also interact with the molecular pathways involved in genetic forms of ALS?

Theme #3: Nuclear Transport Defects in a Novel Form of Neurodegeneration.

We have identified both a mouse model and human populations with gene mutations that result in defects in nucleo-cytoplasmic transport.

  • How do these mutations result in altered nuclear trafficking?
  • What are the interactions of the mutant protein(s) with nuclear pore components?
  • Do these alterations reflect an accelerated aging phenotype of motor neurons?

We are using mouse models, mammalian and human cell culture, and zebrafish models to study these genetic defects in the context of neurodegeneration.

  • Representative Publications
    • Goody MF, Sher RB, Henry CA. 2015. Hanging On For The Ride: Adhesion To The Extracellular Matrix Mediates Cellular Responses In Skeletal Muscle Morphogenesis And Disease. Developmental Biology. 401(1):75-91
    • Heiman-Patterson TD, Blankenhorn EP, Sher RB, Jiang J, Welsh P, Dixon MC, Jeffrey JI, Wong P, Cox GA, Alexander GM. 2015. Genetic Background Effects on Disease Onset and Lifespan of the Mutant Dynactin p150Glued Mouse Model of Motor Neuron Disease PLoS One. 10(3): e0117848
    • Sher RB*, Heiman-Patterson MD* (*co-first Authors), Blankenhorn EA, Jiang J, Alexander G, Deitch JS, Cox GA. 2014. A Major QTL on Mouse Chromosome 17 Resulting in Lifespan Variability in SOD1-G93A Transgenic Mouse Models of Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 15(7-8): 588-600.
    •  Li Z, Wu G, Sher RB, Khavandgar Z, Hermansson M, Cox GA, Doschak MR, Murshed M, Beier F, Vance DE. 2014. Choline Kinase Beta is Required for Normal Endochondral Bone Formation. Biochim Biophys Acta (PMID:24637075).
    •  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
    • 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 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.
    • 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
    • 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 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
    • 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
    • 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
    • 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.