Gender	Male
E-mail	gareth.john@mssm.edu
Education and Training	MA, University of Cambridge, UK
	Post-graduate, University of London, UK
	Post-graduate, University of Cambridge, UK

Gareth John, Ph.D. is Associate Professor at Mount Sinai School of Medicine and is head of the Multiple Sclerosis Research Lab at the Corinne Goldsmith Dickinson Center for MS at Mount Sinai Medical Center.

The John laboratory focuses on mechanisms that regulate the formation and repair of lesions in multiple sclerosis.  The pathological hallmarks of MS are inflammation of the central nervous system, loss of myelin and the oligodendrocytes that produce it, blood-brain barrier breakdown, and reactive astrogliosis.  Loss of myelin (demyelination) is believed to underlie the symptoms of MS early in the disease course, and has been linked to the damage to nerves that occurs later in the disease.  Conversely, myelin repair (remyelination) is frequently observed in lesions early in the course of the disease, and correlates with the return of efficient conduction.  But remyelination gradually fails as MS progresses, although the mechanism underlying this loss of regenerative capacity is not well understood.

Dr. John and his staff are working under five active grants from the NIH, the National MS Society, pharmaceutical companies, and private benefactors.  Their work has been published in Nature Medicine, Journal of Neuroscience, Proceedings of the National Academy of Sciences, and others.  Their studies share a common long-term goal of identifying novel therapeutic strategies for inflammatory demyelinating diseases, particularly MS.  The research program in the laboratory is also collaborative, in that it allows basic science researchers and physicians to interact and work together towards a common goal.

Dr. John received a Master’s degree in Medical Science at the University of Cambridge, England, and received a VetMB degree there as well.  He earned a doctorate degree in Neuroscience at the University of London.  Dr. John was an instructor and research fellow at Albert Einstein College of Medicine, Bronx, NY before joining Mount Sinai as an assistant professor in the department of Neurology in 2003.

Education and Training	MA, University of Cambridge, UK
	Post-graduate, University of London, UK
	Post-graduate, University of Cambridge, UK

Research

Specific Clinical/Research Interests: CNS, glia, astrocyte, inflammation, injury, repair

Summary of Research Studies:
Injury, inflammation or degenerative disease in the central nervous system (CNS) are accompanied by alterations in the morphology and gene expression patterns of astrocytes, the most numerous population of CNS glia. This response is referred to as a reactive astrogliosis, and accumulating evidence suggests that these cells regulate the inflammatory reponse, and further that they represent a significant obstacle to CNS regeneration, both in terms of neurons and the oligodendrocytes that myelinate them. Research in the John laboratory focuses on understanding the molecular profile and functional significance of a reactive astrogliosis, with the ultimate goal of designing novel strategies to restrict neural damage and demyelination, and promote repair within the adult CNS.

Approaches:

Core techniques in use in the laboratory include functional genomics, molecular and cellular biology, and genetically modified (Cre-lox) mouse models.

Project 1.  Notch signaling regulates progenitor differentiation and remyelination in adult CNS.
In the developing CNS, the Notch1 receptor and its ligand Jagged1 regulate the differentiation of myelinating oligodendrocytes and the formation of myelin, but their role in repair of demyelinating lesions in diseases such as multiple sclerosis has remained unresolved.  To address this question, we recently generated a mouse model in which we targeted inactivation of Notch1 to oligodendrocyte progenitor cells (OPC) using Olig1Cre and a new floxed Notch1 allele, Notch112f.  During CNS development, OPC differentiation is potentiated in Olig1Cre:Notch112f/12f mice.  Importantly, in adults, remyelination of demyelinating lesions is also accelerated, at the expense of proliferation within the progenitor population.  These data suggest that Notch1 signaling is one of the mechanisms regulating OPC differentiation during CNS remyelination.  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. 

Project 2.  Loss of endothelial CLN-5 underlies blood-brain barrier disruption in inflamed CNS. 
Breakdown of the blood-brain barrier (BBB) is a significant event in CNS inflammation.  Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms are unresolved.  Recently, we identified as a novel target of VEGF-A the endothelial transmembrane tight junction protein claudin-5 (CLN-5).  Downregulation of CLN-5 accompanies upregulation of VEGF-A and correlates w ith BBB breakdown in EAE, an animal model of CNS inflammatory disease.  In cultures of brain microvascular endothelial cells (BMVEC), VEGF-A specifically downregulates CLN-5 protein and mRNA.  In mouse cerebral cortex, microinjection of VEGF-A disrupts CLN-5 and induces loss of barrier function.  Importantly, in functional studies recombinant CLN-5 protects BMVEC cultures from VEGF-induced paracellular permeability.  These data suggest for the first time that downregulation of CLN-5 by VEGF-A constitutes a significant mechanism in BBB breakdown.  They are the focus of ongoing experiments using Cre-lox mice.  See also Argaw et al.  Proc Natl Acad Sci USA. 2009 Feb 10;106(6) :1977-82.

Project 3.  Interleukin-11 regulates autoimmune demyelination.
Current therapies for multiple sclerosis (MS) target inflammation but do not directly address lesion repair.  Cytokines of the gp130 family regulate survival and differentiation of both neural and immune cells, and using a functional genomics approach we recently identified expression of the family member interleukin-11 (IL-11) in MS plaques.  To determine functional relevance, we have examined mice with EAE, a demyelinating mouse model that mimics many of the clinical and pathologic features of MS.  Importantly, these studies have shown that IL-11 regulates the clinical course and neuropathology of EAE, and that its effects are achieved via a combination of immunoregulation and direct neuroprotection.  IL-11 receptor-alpha null (IL-11Ra-/-) mice display a significant increase in clinical severity and neuropathology of EAE compared with wildtype controls. Inflammation, demyelination, and oligodendrocyte and neuronal loss are all exacerbated in IL-11Ra-/- animals.  Our data suggest that IL-11 signaling may represent a therapeutic avenue to restrict CNS inflammation and potentiate oligodendrocyte survival in autoimmune demyelinating disease.  See also Gurfein et al., J Immunol. 2009 Oct 1;183(7):4229-40.

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.

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.

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, 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 2000 Jun 15; 21(12): 4134-4142.

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, 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.

Zhang Y, Taveggia C, Melendez-Vasquez C, Einheber S, Raine CS, Salzer JL, Brosnan CF, John GR. Interleukin-11 regulates oligodendrocyte survival and maturation, and myelin formation. J Neurosci 2006; 26: 12174-12185.

Argaw AT, Zhang Y, Snyder B, Zhao ML, Kopp N, Lee SC, Raine CS, Brosnan CF, John GR. Interleukin induces blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol 2006; 177: 5574-5584 .

Zhang Y, Raine CS, Brosnan CF, John GR. Interleukin-11: a survival and maturation factor for human oligodendrocytes. J Neurosci 2006; 26: 12174-12184.

Brosnan CF, John GR. Revisiting Notch in remyelination of multiple sclerosis lesions. J Clin Invest 2008; Epub ahead of print.

Argaw AR, Gurfein BT, Zhang Y, Zameer A, Brosnan CF, John GR. Downregulation of endothelial CLN-5 and OCLN is induced by VEGF-A, and correlates with blood-brain barrier permeability in the inflamed CNS. Proc Natl Acad Sci USA;.