Beker Multiple Sclerosis Research Laboratory

Research

The John Laboratory (Beker Multiple Sclerosis Research Laboratory is part of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, the Department of Neurology, and the Friedman Brain Institute. Our research focuses on identifying novel avenues to restrict tissue damage and promote repair in inflammatory and demyelinating CNS conditions, notably multiple sclerosis (MS), neuromyelitis optica (NMO), and viral encephalitis. MS is the most common non-traumatic cause of paralysis in young adults in the US and Europe, the symptoms of which are driven by autoimmune demyelination of CNS white matter, while NMO is a rare but aggressive autoimmune MS-like condition characterized by spinal cord and optic nerve lesions, paralysis, and blindness.

Our research aims to understand the mechanisms underlying lesion pathogenesis and repair in these conditions, and focuses on how the environment within the CNS controls inflammatory lesion size and the potential for repair. We make extensive use of conditional genetic models in which developmental myelin formation, and demyelination and remyelination in adults, are accelerated or impaired. Phenotypes in conditional knockout models developed in the lab are then interrogated using genome-scale analyses of transcription and chromatin occupancy, confocal imaging, and electron microscopy. The goal of this work is to identify novel therapies to prevent lesion formation and protect patient health, and to repair existing damage and promote return of function. Our research is funded by the National Institutes of Health, the National MS Society, the Guthy-Jackson Foundation, pharmaceutical and biotech industry collaborations, and private benefactors.

in vitro co culture model of CNS myelination

In vitro co-culture model of CNS myelination. This image illustrates a CNS co-culture of neurons (green) and myelinating oligodendrocytes (red), in which myelin segments appear as linear yellow profiles. This image appeared on the cover of the August 2011 issue of The Journal of Immunology, accompanying an article from our laboratory. In the article, we showed that the growth factor IL-11 promotes myelin repair in MS models via a balance in activity of Stat3 versus Stat1 signaling. Zhang, J., Y. Zhang, D. J. Dutta, A. T. Argaw, V. Bonnamain, J. Seto, D. A. Braun, A. Zameer, F. Hayot, C. B. Lòpez, C. S. Raine, and G. R. John. 2011.Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11. J. Immunol. 187: 1129–1141. NIHMSID: NIHMS299922 PubMed [journal] PMID:21709156, PMCID: PMC3164308

Projects

Project 1. How does the environment of the CNS control inflammatory lesion size and the potential for repair?

Astrocytes are the most numerous cell type in the mammalian CNS, and respond to inflammation or injury with a graded transcriptional program driven by pro- or anti-inflammatory mediators. These changes, called reactive astrogliosis, profoundly impact surrounding neural and non-neural cells. One of the major goals of our work is to understand the functional impact of reactive astrogliosis on other cell types within the CNS, with a translational focus.

Recently, we have found that an astrocyte-derived family of growth factors, which signal via the gp130 receptor and the transcription factor Stat3, are required for normal CNS white matter formation and myelination, and that these factors act in part via transcriptional activators of the Kruppel-like factor (Klf) family. Conditional inactivation of Stat3 or Klf6 in the precursors of myelinating cells, called oligodendrocyte progenitors, results in failure of CNS myelination and complete absence of white matter formation. We are currently investigating whether the Stat3-Klf6 axis is also required for successful repair of myelin and return of function in models of MS.

Conditional inactivation of Stat3-Klf6 signaling causes failure of CNS myelination. Pseudocolored electron micrograph of spinal cord white matter tracts from a 19 day old mouse pup in which the transcriptional activator Klf6 has been conditionally inactivated in the progenitors of myelinating cells (oligodendrocyte progenitor cells). The photograph shows unmyelinated axons (colored circles) surrounded by glial processes (shown in pale blue). At this stage of development, axons in spinal cord white matter should be fully myelinated, but our work shows that inactivation of Stat3-Klf6 signaling results in complete failure of CNS myelination and white matter formation. Magnification, x2000. This image is taken from our publication: Laitman BM, Asp L, Mariani JN, Kramer EG, Pedre X, Dutta DJ, Lee Y-M, Liu J, Zhang J, Argaw AT, Zaslavsky E, Braun DG, Pham T, Horng S, Hara Y, Lu QR, Narla G, Raine CS, Casaccia P, Friedman SL, John GR. The transcriptional activator Krüppel-like factor-6 is required for CNS myelination. PLoS Biology, In Press.

Project 2. What are the mechanisms controlling entry of inflammatory cells into the CNS parenchyma?

Inflammatory lesions in conditions such as MS and NMO are characterized by entry of inflammatory cells and soluble factors (such as antibodies) into the CNS parenchyma. These events are associated with breakdown of the blood-brain barrier (BBB), which in healthy adults separates the CNS from the rest of the body. The BBB is an endothelial barrier, but its integrity is controlled by other cell types, notably astrocytes and pericytes.

Importantly, our research has identified reactive astrocytes as key controllers of BBB permeability in inflammatory lesions, acting via plasticity factors such as VEGF-A and ECGF1/TP. Most notably, we have found that genetic or therapeutic blockade of these astrocyte-derived factors limits BBB disruption and inflammatory cell and antibody entry, and reduces neurologic deficit in models of MS. These studies have generated an FDA-approved phase Ib clinical trial testing the impact of VEGF-A blockade on disease exacerbation in NMO patients (ClinicalTrials.gov: NCT01777412). We are currently investigating the molecular mechanisms by which reactive astrocytes regulate BBB permeability, and whether they also directly regulate leukocyte migration in inflammatory CNS lesions.

Astrocytes are key regulators of endothelial permeability in the adult CNS. Three-dimensional confocal image of adult mouse cerebral cortex immunostained to show astrocytes (in green) and microvascular endothelial cells (in red). Note the intimate contact between the two cell types. Our research has helped to show that astrocytes are critical regulators of endothelial permeability in the mammalian CNS, and as such play a key role in controlling entry of inflammatory cells into the brain in conditions such as multiple sclerosis. Magnification, X200. This image is taken from our publication: Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. Journal of Clinical Investigation. 2012; 122(7):2454-68. PubMed [journal] PMID: 22653056, PMCID: PMC3386814, and image on JCI Facebook page as the June 2012 Scientific Show Stopper.

Contact Us

John Laboratory
Gareth R John, PhD
Professor, Neurology
Location
Lab: Annenberg 14-86
Phone
Lab: 212.659.5989
Fax: 212.348.1310
Email

Featured

The Journal of Immunology Aug 2011

Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11.Zhang, J., Y. Zhang, D. J. Dutta, A. T. Argaw, V. Bonnamain, J. Seto, D. A. Braun, A. Zameer, F. Hayot, C. B. Lòpez, C. S. Raine, and G. R. John. 2011.

In this study, we demonstrate that these effects of IL-11 are mediated via differential regulation of apoptosis in oligodendrocytes versus Ag-presenting dendritic cells (DCs), and are dependent on lineage-specific activity of the transcription factors Stat1 versus Stat3.

Publications

2016

Lee YA, Noon LA, Lee T-F, Akat KM, Chou H-I, Berres M-L, Fiel MI, Gordon R, Pfleger C, Germain D, Khambu B, Yin X-M, Campbell K, Yue Z, Kramer E, John G, Czaja MJ , Hoshida Y, Friedman SL. Hepatic growth regulation and carcinogenesis are linked to autophagy through the hippo tumor suppressor pathway. Submitted.


Moyon S, Huynh JL, Dutta D, Zhang F, Yoo S, Ma D, Yoo S, Lawrence R, Wegner M, John GR, Emery B, Svaren J, Lubetzki C, Franklin RJ, Fan G, Zhu J, Dupree JL, Casaccia P. Functional characterization of DNA methylation in the oligodendrocyte lineage. Submitted.


Laitman BM, Asp L, Mariani JN, Kramer EG, Pedre X, Dutta DJ, Lee Y-M, Liu J, Zhang J, Argaw AT, Zaslavsky E, Braun DG, Pham T, Horng S, Hara Y, Lu QR, Narla G, Raine CS, Casaccia P, Friedman SL, John GR. The transcriptional activator Krüppel-like factor-6 is required for CNS myelination. PLoS Biology, In Press.

2015

Laitman BM, John GR. Understanding How Exercise Promotes Cognitive Integrity in the Aging Brain. PLoS biology. 2015; 13(11):e1002300. PubMed [journal] PMID: 26558429, PMCID: PMC4641709.


Melamed E, Levy M, Waters PJ, Sato DK, Bennett JL, et al. Update on biomarkers in neuromyelitis optica. Neurology, Neuroimmunology & Neuroinflammation. 2015; 2(4):e134. PubMed [journal] PMID: 26236760, PMCID: PMC4516398


Kremer S, Renard F, Achard S, Lana-Peixoto MA, Palace J, et al. Use of Advanced Magnetic Resonance Imaging Techniques in Neuromyelitis Optica Spectrum Disorder. JAMA Neurology. 2015; 72(7):815-22. PubMed [journal] PMID: 26010909


Chapouly C, Tadesse Argaw A, Horng S, Castro K, Zhang J, et al. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions. Brain. 2015; 138(Pt 6):1548-67. PubMed [journal] PMID: 25805644, PMCID: PMC4614128 (and accompanying image on journal website, linked). http://brain.oxfordjournals.org/content/brain/138/6/1548/F1.large.jpg?width=800&height=600


Kim HJ, Paul F, Lana-Peixoto MA, Tenembaum S, Asgari N, Palace J, Klawiter EC, Sato DK, de Seze J, Wuerfel J, Banwell BL, Villoslada P, Saiz A, Fujihara K, Kim SH; Guthy-Jackson Charitable Foundation NMO International Clinical Consortium & Biorepository. Neurology. 2015 Mar 17;84(11):1165-73. doi: 10.1212/WNL.0000000000001367. Epub 2015 Feb 18. Review. PMID: 25695963

Smith ES, Jonason A, Reilly C, Veeraraghavan J, Fisher T, et al. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiology of Disease. 2015; 73:254-68. PubMed [journal] PMID: 25461192

2014

Dutta DJ, Zameer A, Mariani JN, Zhang J, Asp L, et al. Combinatorial actions of Tgfβ and Activin ligands promote oligodendrocyte development and CNS myelination. Development. 2014; 141(12):2414-28. PubMed [journal] PMID:24917498, PMCID: PMC4050697


Rusielewicz T, Nam J, Damanakis E, John GR, Raine CS, et al. Accelerated repair of demyelinated CNS lesions in the absence of non-muscle myosin IIB. Glia. 2014; 62(4):580-91. NIHMSID: NIHMS614584 PubMed [journal] PMID: 24470341, PMCID:PMC4135430.

2012

Brück W, Pförtner R, Pham T, Zhang J, Hayardeny L, et al. Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta neuropathologica. 2012; 124(3):411-24. PubMed [journal] PMID: 22766690, PMCID: PMC3422618


Argaw AT, Asp L, Zhang J, Navrazhina K, Pham T, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. Journal of Clinical Investigation. 2012; 122(7):2454-68. PubMed [journal] PMID: 22653056, PMCID: PMC3386814 (and image on JCI Facebook page as the June 2012 Scientific Show Stopper, linked below). https://www.facebook.com/jclininvest/photos/a.187145287988684.33467.165951396774740/3891557 17787639/?type=3&theater


John GR. Investigation of astrocyte – oligodendrocyte interactions in human cultures. Methods in Molecular Biology (Clifton, N.J.). 2012; 814:401-14. NIHMSID: NIHMS350869 PubMed [journal] PMID: 22144322, PMCID: PMC3299010. (and cover, linked below)

2011

Zhang J, Kramer EG, Asp L, Dutta DJ, Navrazhina K, et al. Promoting myelin repair and return of function in multiple sclerosis. FEBS Letters. 2011; 585(23):3813-20. NIHMSID: NIHMS322724 PubMed [journal] PMID: 21864535, PMCID:PMC3223332.


Gaupp S, Arezzo J, Dutta DJ, John GR, Raine CS. On the occurrence of hypomyelination in a transgenic mouse model: a consequence of the myelin basic protein promoter? Journal of Neuropathology and Experimental Neurology. 2011; 70(12):1138-50. NIHMSID: NIHMS336716 PubMed [journal] PMID: 22082665, PMCID:PMC3774272.


Zhang J, Zhang Y, Dutta DJ, Argaw AT, Bonnamain V, et al. Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11. Journal of Immunology (Baltimore, Md.: 1950). 2011; 187(3):1129-41. NIHMSID: NIHMS299922 PubMed [journal] PMID:21709156, PMCID: PMC3164308 (and cover, linked). http://www.jimmunol.org/content/187/3.cover-expansion


Zhang J, Kramer EG, Mahase S, Dutta DJ, Bonnamain V, et al. Targeting oligodendrocyte protection and remyelination in multiple sclerosis. The Mount Sinai Journal of Medicine, New York. 2011; 78(2):244-57. NIHMSID: NIHMS263857 PubMed [journal] PMID: 21425268, PMCID: PMC3074606

Meet the Team

Sam Horng, MD PhD

Sam Horng, MD PhD

Assistant Professor

Sam.Horng@mssm.edu
John Mariani BA

John Mariani BA

PhD Student

Johnmariani@gmail.com
Candice Chapouly PhD

Candice Chapouly PhD

Postdoctoral Fellow

Candice.chapouly@mssm.edu
Anthony Therattil BA

Anthony Therattil BA

Research Technician

anthony.therattil@mssm.edu
Setsu Sawai MD PhD

Setsu Sawai MD PhD

Postdoctoral Fellow

Setsu.sawai@mssm.edu
Ari Dienel

Ari Dienel

Postdoctoral Fellow

Ben Laitman BA

Ben Laitman BA

MSTP Student

Benlaitman@gmail.com