Gareth R. John
- ASSOCIATE PROFESSOR Neurology
MA, University of Cambridge, UK
VetMB, University of Cambridge, UK
PhD, University of London, UK
- Dr. Gareth John is head of the Multiple Sclerosis Research Laboratory at the Corinne Goldsmith Dickinson Center for MS in the Mount Sinai School of Medicine.
The John laboratory researches mechanisms that control lesion formation and repair in inflammatory diseases of the central nervous system (CNS). Our work focuses particularly on identifying new therapies for multiple sclerosis (MS), an autoimmune demyelinating disease of the brain and spinal cord that is the most common nontraumatic cause of paralysis in young adults in the US.
In the normal CNS, myelin wraps around nerves and greatly increases the efficiency of information transmission in the brain and spinal cord. Loss of myelin (demyelination) and destruction of the oligodendrocytes that make it are the major causes of the early symptoms of MS, and have been strongly linked to the damage to nerves and permanent disability that occur in the later stages of the disease. Myelin repair (remyelination) is seen in early MS lesions, and is associated with return of nerve conduction, and clinical recovery. However, remyelination gradually fails as MS progresses. Our work examines the mechanisms underlying this loss of regenerative capacity, with the aim of identifying new treatments to enhance repair and return of function.
Work from the laboratory has been published in peer-reviewed journals including Nature Medicine, Proceedings of the National Academy of Sciences, and the Journal of Neuroscience. Laboratory members are currently funded by grants from the National Institutes of Health, the National Multiple Sclerosis Society, Teva Neuroscience, and private benefactors including the Jayne and Harvey Beker Foundation.
Andleeb Zameer, PhD - Instructor
Azeb Tadesse Argaw, PhD - Instructor
Jingya Zhang, PhD - Postdoctoral Fellow
Virginie Bonnamain, PhD - Postdoctoral Fellow
Dipankar Dutta - PhD Thesis Student
For more information about the John Lab: http://www.mssm.edu/research/labs/beker-multiple-sclerosis-research-laboratories
Specific Clinical/Research Interests
CNS, glia, astrocyte, inflammation, injury, repair
Members of the laboratory research the mechanisms that control the extent of damage and the capacity for repair in inflammatory diseases of the brain and spinal cord. We have a particular focus on identifying novel treatments to enhance lesion repair in the autoimmune demyelinating disease multiple sclerosis (MS). Core techniques include cDNA microarray analysis, and culture of primary cells including oligodendrocyte progenitors, astrocytes, and multipotent neural progenitors. To confirm the relevance of our findings in the adult brain and spinal cord, we use conditional knockout (Cre-lox) models, and stereotactic microinjection of recombinant vectors into adult cerebral cortices.
2. Interleukin-11 regulates autoimmune demyelination in models of multiple sclerosisCurrent therapies for multiple sclerosis target inflammation, but do not directly address repair of lesions, and clinical recovery. Inflammatory factors of the gp130 cytokine family are known to regulate the survival and differentiation of both neural and inflammatory cells. We have investigated the roles of members of this family in inflammatory conditions of the brain and spinal cord, to determine if they represent a means to enhance neuroprotection and regulate inflammation.
Recently, using a cDNA microarray-based approach, we identified expression of the gp130 cytokine interleukin-11 (IL-11) in models of CNS inflammation, and in multiple sclerosis lesions. To determine the functional relevance of these findings, we have now examined mice with experimental autoimmune encephalomyelitis (EAE), a demyelinating model that mimics many of the features of MS. Importantly, these studies have shown that IL-11 regulates the clinical course and pathology of EAE. We have found that mice lacking the IL-11 receptor (IL-11Ra-/-) mice display significantly exacerbated neurological signs and neuropathology of EAE compared with controls. Inflammation, demyelination, and oligodendrocyte and neuronal loss are all significantly worsened in IL-11Ra-/- animals.
These findings identify an important mechanism that restricts CNS inflammation and improves the survival of myelin-forming oligodendrocytes in an inflammatory demyelinating model of MS. See also Gurfein et al., J Immunol. 2009 Oct 1;183(7):4229-40.
1. Notch signaling regulates repair of demyelinating lesions in the adult CNSIn the developing brain and spinal cord, the Notch1 receptor and its ligand Jagged1 constitute an important mechanism controlling the differentiation of myelinating oligodendrocytes, and myelin formation. However, the role played by this pathway in repair of demyelinating lesions in diseases such as multiple sclerosis has remained unresolved. To address this question, we recently generated a new conditional knockout mouse in which we targeted inactivation of the Notch1 receptor to oligodendrocyte progenitor cells (OPC) using Olig1Cre and a new conditional Notch1 allele, Notch112f. We found that in Olig1Cre:Notch112f/12f mice, the behavior of OPCs is shifted towards differentiation during CNS development. Importantly, in adults, repair of demyelinating lesions is accelerated in these mice, at the expense of proliferation within the progenitor population. These findings suggest that Notch1 signaling is one of the mechanisms regulating OPC differentiation during CNS remyelination and recovery of function. Thus, Notch1 may represent a potential therapeutic avenue for lesion repair in demyelinating diseases such as multiple sclerosis. See also Zhang et al., Proc Natl Acad Sci USA. 2009 Nov 10;106(45):19162-7.
3. Blood-brain barrier breakdown in inflammatory disease of the CNSIn the normal adult CNS, the blood-brain barrier (BBB) separates the circulatory system from the environment of the brain and spinal cord, allowing conditions within the CNS to be optimized for efficient nerve transmission. Breakdown of the BBB occurs early in the course of most inflammatory CNS conditions, and correlates with permanent CNS damage in diseases such as multiple scleros. Inhibiting BBB disruption may represent a means to restrict the extent of permanent damage in CNS inflammation.
Recently, we and others found that the growth factor VEGF-A is an important inducer of BBB breakdown in the injured or inflamed brain and spinal cord. We have now identified an important mechanism underlying its action. Integrity of the BBB depends on tight junctions within the CNS microvasculature, and we have found that VEGF-A disrupts these junctions via downregulation of two key proteins, claudin-5 (CLN-5) and occludin (OCLN). Downregulation of CLN-5 accompanies upregulation of VEGF-A and correlates with BBB breakdown in animal models of CNS inflammation. In cultures of brain microvascular endothelium, VEGF-A specifically downregulates CLN-5 and OCLN protein and RNA. In mouse cerebral cortex, microinjection of VEGF-A disrupts CLN-5 and induces loss of barrier function. Importantly, using rescue studies we have shown that recombinant CLN-5 protects microvascular endothelial cells from VEGF-induced permeability.
These findings identify a new mechanism underlying BBB breakdown in the inflamed CNS, and may represent a means to restrict BBB disruption and CNS damage in diseases such as MS. See also Argaw et al. Proc Natl Acad Sci USA. 2009 Feb 10;106(6) :1977-82.
Zhang Y, Zhang J, Navrazhina K, Argaw AT, Zameer A, Gurfein BT, Brosnan CF, John GR. TGFbeta1 induces Jagged1 expression in astrocytes via ALK5 and Smad3 and regulates the balance between oligodendrocyte progenitor proliferation and differentiation.. Glia 2010 Feb 18;: E-pub.
Zhang Y, Argaw A, Gurfein B, Zameer A, Snyder B, Ge C, Lu Q, Rowitch D, Raine C, Brosnan C, John G. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination. Proc Natl Acad Sci USA 2009 Nov 10; 106(45): 19162-19167.
Gurfein BT, Zhang Y, Lopez CB, Argaw AT, Zameer A, Moran TM, John GR. IL-11 regulates autoimmune demyelination.. J Immunol. 2009 Oct 1; 183(7): 4229-4240.
Argaw AR, Gurfein BT, Zhang Y, Zameer A, Brosnan CF, John GR. VEGF- Mediated disruption of endothial CLN-5 promotes blood-brain barrier breakdown.. Proc Natl Acad Sci USA 2009 Feb; 106(6): 1977-1982.
Brosnan CF, John GR. Revisiting Notch in remyelination of multiple sclerosis lesions. J Clin Invest 2009 Jan; 119(1): 10-13.
Zhang Y, Taveggia C, Melendez-Vasquez C, Einheber S, Raine CS, Salzer JL, Brosnan CF, John GR, . Interleukin-11 potentiates oligodendrocyte survival and maturation, and myelin formation.. J Neurosci 2006 Nov. 22; 26(47): 12174-12185.
Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR. IL-1beta induces blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol 2006 Oct 15; 177(8): 5574-5584.
Omari KM, John GR, Sealfon SC, Raine CS. CXC chemokine receptors on human oligodendrocytes: implications for multiple sclerosis. Brain 2005 May; 128(Pt 5): 1003-1015.
Rivieccio MA, John GR, Song X, Suh HS, Zhao Y, Lee SC, Brosnan CF. The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture.. J Immunol 2005 Mar 15; 174(6): 3719-3726.
John GR, Chen LF, Rivieccio MA, Melendez-Vasquez CV, Hartley A, Brosnan CF. Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis. J Neurosci 2004 Mar 17; 24(11): 2837-2845.
John GR, Shankar SL, Shafit-Zagardo B, Massimi A, Lee SC, Raine CS, Brosnan CF. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat Med 2002 Oct; 8(10): 1115-1121.
John GR, Simpson JE, Woodroofe MN, Lee SC, Brosnan CF. Extracellular nucleotides differentially regulate interleukin-1beta signaling in primary human astrocytes: implications for inflammatory gene expression. J Neurosci 2001 Jun 15; 21(12): 4134-4142.
Liu JS H, John GR, Sikora A, Hua LL, Lee SC, Brosnan CF. Modulation of interleukin-1beta and tumor necrosis factor alpha signaling by P2 purinergic receptors in human fetal astrocytes. J Neurosci 2000 Jul 15; 20(14): 5292-5299.
Duffy HS, John GR, Lee SC, Brosnan CF, Spray DC. Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1beta in primary human fetal astrocytes. J Neurosci 2000 Dec 1; 20(23): RC114.
John GR, Scemes E, Suadicani SO, Liu JS, Charles PC, Lee SC, Spray DC, Brosnan CF. IL-1beta differentially regulates calcium wave propagation between primary human fetal astrocytes via pathways involving P2 receptors and gap junction channels. Proc Natl Acad Sci U S A 1999 Sep 28; 96(20): 11613-11618.
Physicians and scientists on the faculty of the Icahn School of Medicine at Mount Sinai often interact with pharmaceutical, device and biotechnology companies to improve patient care, develop new therapies and achieve scientific breakthroughs. In order to promote an ethical and transparent environment for conducting research, providing clinical care and teaching, Mount Sinai requires that salaried faculty inform the School of their relationships with such companies.
Below are financial relationships with industry reported by Dr. John during 2012 and/or 2013. Please note that this information may differ from information posted on corporate sites due to timing or classification differences.
Other Activities: Examples include, but are not limited to, committee participation, data safety monitoring board (DSMB) membership.
- Novartis; Teva Pharmaceutical Industries Ltd.
Mount Sinai's faculty policies relating to faculty collaboration with industry are posted on our website at http://icahn.mssm.edu/about-us/services-and-resources/faculty-resources/handbooks-and-policies/faculty-handbook. Patients may wish to ask their physician about the activities they perform for companies.
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