About Us

The Beker Multiple Sclerosis Research Lab (or John Laboratory) researches mechanisms controlling lesion formation and repair in inflammatory diseases of the central nervous system (CNS). Our work focuses on identifying new therapies for multiple sclerosis (MS), a 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 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 functional recovery. However, remyelination gradually fails as MS progresses. Our work examines the mechanisms underlying myelin repair, with the aim of identifying new treatments to enhance return of function.

Examples of recent research projects include:

Figure 1. Inhibition of Notch1 activity in oligodendrocytes potentiates myelin formation.
Myelinating co-cultures of oligodendrocytes (MBP+, red) and dorsal root ganglion neurons (NF+, green). After 14 days of co-culture, myelin segments are observed as linear MBP+ profiles (arrowheads) extending along NF+ nerve fibers. In this experiment, short interfering RNAs (siRNAs) for the Notch1 receptor were introduced into oligodendrocytes prior to co-culture. After 14 days, co-cultures receiving Notch1 siRNA-treated oligodendrocytes display significantly increased myelin formation.

Notch signaling regulates repair of demyelinating lesions in the adult CNS.
In the developing brain and spinal cord, activity of the Notch1 receptor is an important mechanism controlling the differentiation of myelinating oligodendrocytes, and myelin formation (Figure 1). 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, repair of demyelinating lesions is accelerated. 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.

Figure 2. Astrocytic endfeet contact microvascular endothelium in the adult CNS.
A three-dimensional rendering of a confocal image from the forebrain of an 11wk adult mouse. The section has been immunostained for the CNS-specific endothelial tight junction protein claudin-5 (CLN-5, red) and the astrocytic marker GFAP (green) and counterstained with DAPI (nuclei, blue). CLN-5 is a major determinant of the properties of the blood-brain barrier in the adult CNS, and localizes to CNS microvessels. Staining for GFAP illustrates the close proximity of these vessels to astrocytic endfeet, which are strongly implicated in regulation of the properties of the barrier.

Blood-brain barrier breakdown in inflammatory disease of the CNS.
In the normal adult CNS, the blood-brain barrier (BBB) separates the circulatory system from the brain and spinal cord, optimizing conditions in the CNS for efficient nerve transmission (Figure 2). 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 sclerosis.

We have found that the growth factor VEGF-A is an important inducer of BBB breakdown, and have now identified an important mechanism underlying its action. Integrity of the BBB depends on tight junctions within the CNS microvessels, and we have found that VEGF-A disrupts these junctions via downregulation of two key proteins, claudin-5 (CLN-5) and occludin (OCLN).

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 multiple sclerosis.
See also Argaw et al. Proc Natl Acad Sci USA. 2009 Feb 10;106(6) :1977-82.

Figure 3. IL-11Rα-/- mice with EAE display exacerbated demyelination.
Confocal images of spinal cord sections from adult mice. These images compare the pathology of experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis) in mice with a targeted mutation for the interleukin-11 receptor-α (IL-11Rα-/-) and controls. The sections have been immunostained for myelin basic protein (MBP, green), and counterstained with DAPI (nuclei, blue). Loss of myelin (demyelination, arrowheads) is more extensive in the IL-11Rα-/- mutant mice than in controls. In multiple sclerosis, demyelination is associated with loss of function in affected nerves. Our data show that loss of IL-11 exacerbates demyelination and functional loss in mice with EAE.

Interleukin-11 regulates autoimmune demyelination in models of multiple sclerosis.
Current therapies for multiple sclerosis target inflammation, but do not address repair and return of function. Inflammatory factors of the gp130 cytokine family are known to regulate the survival and differentiation of both neural and inflammatory cells. We have investigated members of this family to determine if they represent a means to enhance neuroprotection and regulate inflammation in MS. Recently, we identified expression of the gp130 cytokine interleukin-11 (IL-11) in models of CNS inflammation, and in multiple sclerosis lesions. We have now examined the role of IL-11 in mice with experimental autoimmune encephalomyelitis (EAE), a demyelinating model that mimics many of the features of MS. We have found that mice lacking the IL-11 receptor (IL-11Rα-/-) mice display significantly exacerbated neurological signs and neuropathology of EAE compared with controls (Figure 3).

These findings identify a new 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.