...Changing The World

Michelson Post-Injury Glial Scarring Initiative [PVA].

Project Description

Grantee Year Issue Program
Beneficiaries Paralyzed Veterans of America 2006 Research Spinal Cord Regeneration Yale Research Project
2010-09/14 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 1
2011-12/08 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 2
2013-05/06 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 3
2015-03/18 Glial Scarring in CNS Injury Yale Center Year 4
Grantee Beneficiaries Paralyzed Veterans of America
Year Issue Program
2006 Research Spinal Cord Regeneration Yale Research Project
2010-09/14 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 1
2011-12/08 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 2
2013-05/06 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 3
2015-03/18 Glial Scarring in CNS Injury Yale Center Year 4
Grantee Beneficiaries Paralyzed Veterans of America
Year Issue Program
2006 Research Spinal Cord Regeneration Yale Research Project
2010-09/14 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 1
2011-12/08 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 2
2013-05/06 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 3
2015-03/18 Glial Scarring in CNS Injury Yale Center Year 4
Grantee Beneficiaries Paralyzed Veterans of America
Year Issue Program
2006 Research Spinal Cord Regeneration Yale Research Project
2010-09/14 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 1
2011-12/08 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 2
2013-05/06 Nerve regeneration, demyelination of the nerves, & chronic pain Yale Center Year 3
2015-03/18 Glial Scarring in CNS Injury Yale Center Year 4

The Yale Center for Neuroscience and Regeneration Research was established in 1987 as partnership between the Paralyzed Veterans of America [PVA] and Yale University. Within the Research Center, a highly collaborative, focused multidisciplinary team of 40 scientists—molecular and cell biologists, physiologists, biophysicists, pharmacologists, molecular geneticists, pain researchers, stem cell biologists and clinicians—is developing new therapies, and cures, to benefit people with central nervous system injury and disease. The Center’s research focuses on preservation and restoration of neurological function through the application of novel approaches as revealed by the genomic revolution. Funding from the Michelson Medical Research Foundation allows the Center to research ways to control glial scarring, so as to enhance functional recovery after damage to the spinal cord due to traumatic injury, and in diseases such as multiple sclerosis (MS).

Glial Scarring Beneficial or Deleterious?

Damage to the spinal cord activates astrocytes to become reactive—a process known as astrogliosis that leads to glial scar formation. Controversy exists on whether glial scarring is beneficial or deleterious to repair of the damaged spinal cord, and thus merits in-depth investigation. The Yale Research Center has shown that reactive astrocytes within active and chronic human MS lesions display increased levels of sodium channel protein Nav1.5 (Black JA et al., 2010). Their recent studies demonstrate that blocking of Nav1.5 channels can attenuate reactive astrogliosis in an in vitro model of glial scarring (Pappalardo LW et al., 2014), and suggest that Nav1.5 may play an important role in glial scarring. As a next step, through support from Michelson Medical Research Foundation, the Center is utilizing conditional gene knock-out technology to develop a model in which to study the contribution of Nav1.5 to astrogliosis and glial scar formation in vivo. Availability of such a model would permit closer examination of the effects of reduced glial scarring on recovery after spinal cord damage, and hasten the pace toward clinical translation.

Stephen G. Waxman, MD, PhD

“Each month we learn something new about the injured nervous system, and we remind ourselves that our research can make a difference for real people. In a realistic sense, we are delivering hope,” Stephen G. Waxman, MD, PhD; Director, Yale Center for Neuroscience and Regeneration Research.

Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions [Dr. Joel A. Black, Yale University).
24 hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).
Figure 1: Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions. GFAP positive astrocyte (green) within control tissue does not exhibit Nav1.5 labelling. In contrast, GFAP positive astrocyte within an active multiple sclerosis lesion displays robust Nav1.5 labelling (red). Merged image of GFAP and Nav1.5 is yellow. GFAP is a biomarker for the visualization of reactive astrocytes (Courtesy Dr. Joel A. Black, Yale University).
Figure 2: Astrocyte response to injury is suppressed by Nav1.5 knockdown. (Left) Quantitative real-time RT-PCR shows Nav1.5 mRNA expression in cells treated with Nav1.5 siRNA was decreased by approximately 70% compared to untreated control (NT siRNA), indicating successful knockdown of Nav1.5. (Right) Twenty-four hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).
Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions [Dr. Joel A. Black, Yale University).
24 hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).
Figure 1: Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions. GFAP positive astrocyte (green) within control tissue does not exhibit Nav1.5 labelling. In contrast, GFAP positive astrocyte within an active multiple sclerosis lesion displays robust Nav1.5 labelling (red). Merged image of GFAP and Nav1.5 is yellow. GFAP is a biomarker for the visualization of reactive astrocytes (Courtesy Dr. Joel A. Black, Yale University).
Figure 2: Astrocyte response to injury is suppressed by Nav1.5 knockdown. (Left) Quantitative real-time RT-PCR shows Nav1.5 mRNA expression in cells treated with Nav1.5 siRNA was decreased by approximately 70% compared to untreated control (NT siRNA), indicating successful knockdown of Nav1.5. (Right) Twenty-four hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).
Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions [Dr. Joel A. Black, Yale University).

Figure 1: Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions. GFAP positive astrocyte (green) within control tissue does not exhibit Nav1.5 labelling. In contrast, GFAP positive astrocyte within an active multiple sclerosis lesion displays robust Nav1.5 labelling (red). Merged image of GFAP and Nav1.5 is yellow. GFAP is a biomarker for the visualization of reactive astrocytes (Courtesy Dr. Joel A. Black, Yale University).


24 hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).

Figure 2: Astrocyte response to injury is suppressed by Nav1.5 knockdown. (Left) Quantitative real-time RT-PCR shows Nav1.5 mRNA expression in cells treated with Nav1.5 siRNA was decreased by approximately 70% compared to untreated control (NT siRNA), indicating successful knockdown of Nav1.5. (Right) Twenty-four hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).

Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions [Dr. Joel A. Black, Yale University).

Figure 1: Sodium channel Nav1.5 expression in astrocytes within control tissue and active multiple sclerosis lesions. GFAP positive astrocyte (green) within control tissue does not exhibit Nav1.5 labelling. In contrast, GFAP positive astrocyte within an active multiple sclerosis lesion displays robust Nav1.5 labelling (red). Merged image of GFAP and Nav1.5 is yellow. GFAP is a biomarker for the visualization of reactive astrocytes (Courtesy Dr. Joel A. Black, Yale University).


24 hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).

Figure 2: Astrocyte response to injury is suppressed by Nav1.5 knockdown. (Left) Quantitative real-time RT-PCR shows Nav1.5 mRNA expression in cells treated with Nav1.5 siRNA was decreased by approximately 70% compared to untreated control (NT siRNA), indicating successful knockdown of Nav1.5. (Right) Twenty-four hours after the scratch injury, exposure to Nav1.5 siRNA treatment attenuated closure of the scratch wound to approximately 45% compared to control (Courtesy Dr. Laura West, Yale University).

References

  • Pappalardo LW, Samad OA, Black JA, Waxman SG. Voltage-gated sodium channel Nav 1.5 contributes to astrogliosis in an in vitro model of glial injury via reverse Na(+)/Ca(2+) exchange. Glia. 2014 Jul; 62(7):1162-75. doi: 10.1002/glia.22671. Epub 2014 Apr 17.
  • Black JA, Newcombe J, Waxman SG. Nav1.5 sodium channels in macrophages in multiple sclerosis lesions. Mult Scler. 2013 Apr; 19(5):532-42. doi: 10.1177/1352458512460417. Epub 2012 Sep 4.
  • Black JA, Waxman SG. Sodium channels and microglial function. Exp Neurol. 2012 Apr; 234(2):302-15. doi: 10.1016/j.expneurol.2011.09.030. Epub 2011 Oct 1.
  • Black JA, Newcombe J, Waxman SG. Astrocytes within multiple sclerosis lesions upregulate sodium channel Nav1.5. Brain. 2010 Mar; 133(Pt 3):835-46. doi: 10.1093/brain/awq003. Epub 2010 Feb 10.

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