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Neuroscience Graduate Program at UCSF

Faculty - Linda Noble, Ph.D.

Injury and Repair Mechanisms in the CNS


Research Description

Traumatic brain and spinal cord injuries often result in permanent disabilities that can profoundly affect the quality of life.  The extent of functional recovery after either traumatic brain or spinal cord injury is a consequence of the initial mechanical destruction of tissue and of secondary factors that collectively contribute to additional tissue damage.  The challenge is to carefully define these factors, determine the time course of their expression, and to develop therapeutic interventions that target their temporal “window” of expression.  To address these complex objectives, we have developed and characterized reproducible models of traumatic brain and spinal cord injury in the rodent that accurately mimic the human condition.  These models have been used to recently study the role of matrix metalloproteinases in both the acutely and chronically injured spinal cord and to address the unique vulnerability of the immature brain to traumatic brain injury.

Spinal cord injury.  We have shown that matrix metalloproteinases (MMPs), a family of zinc and calcium requiring endopeptidases, play differing roles in the acutely injured spinal cord and during wound healing.  Strategies to reduce MMP activity and in particular MMP-9 in the acutely injured cord result in stabilization of the blood-spinal cord barrier, reduced leukocyte infiltration, and impaired motor recovery.  However, recent studies show that these beneficial effects are lost if MMP blockade is extended beyond the first 3 days post injury into the period of wound healing.  The contributions of MMPs to acute injury responses and wound healing events are dependent upon which MMPs are expressed, when they are expressed, where they are expressed, and how much is being expressed.  Our studies, which have focused on the gelatinases (MMP-9 and MMP-2), illustrate these points.  MMP-9 activity is limited to the acutely injured spinal cord, whereas MMP-2 activity peaks during wound healing.  Studies, using MMP-9 and MMP-2 null mice, have shown one (MMP-9) to mediate tissue injury and limit motor recovery while the other (MMP-2) modulates glial scar formation.  Ongoing studies, using both pharmacologic and genetic approaches are intended to more closely examine how these MMPs interact in the injured spinal cord.  We are particularly interested in their contributions to leukocyte trafficking, angiogenesis, and remodeling of the extracellular matrix. 

Brain injury.  Although there has been substantial research to understand the neurobiologic basis for persistent impaired cognitive and motor deficits after traumatic brain injury in the adult, less attention has been directed toward the brain-injured child.  Clinical data suggest that children less than 4 years of age exhibit more cognitive deficits as they mature, than older children.  One explanation for this increased vulnerability may be related to the timing of the injury, which occurs during the critical period of development.  We have developed and characterized a model of traumatic brain injury in the young mouse that results in both cortical and subcortical neuronal injury and an overt cognitive deficit.  Two significant findings have resulted from these recent studies.  First, there is clear evidence that vulnerability is related to the reduced antioxidant capacity of the developing brain.  Second, neuronal loss is not limited to the acutely injured brain but rather extends over a period of time during brain maturation.  Importantly, cognitive deficits are delayed in onset.  They are not apparent by 2 weeks post injury but rather coincide with brain maturation.  These exciting findings suggest that there may be an extended therapeutic window of time to treat the brain-injured child.  Our current studies focus on early inflammation and antioxidant reserves as determinants of structural and cognitive recovery after brain injury

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Current Projects

See Research Description

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Lab Members

Hita Adwanikar, Postdoctoral Fellow
Adanma Ekeledo, Research Associate
Thomas Fandel, Research Specialist
Sang Mi Lee, Postdoctoral Fellow
Alpa Trivedi, Assistant Researcher/ Molecular Biologist
Haoqian Zhang, Postdoctoral Fellow

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Selected Publications

Link to Publications via PubMed

Hsu JY, McKeon R, Goussev S, Werb Z, Lee JU, Trivedi A, Noble-Haeusslein LJ. Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J Neurosci 2006;26(39):9841-50.

Pullela R, Raber J, Pfankuch T, Ferriero DM, Claus CP, Koh SE, Yamauchi T, Rola R, Fike JR, Noble-Haeusslein LJ. Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments. Dev Neurosci 2006;28(4-5):396-409.

Lin Y, Vreman HJ, Wong RJ, Tjoa T, Yamauchi T, Noble-Haeusslein LJ. Heme oxygenase-1 stabilizes the blood-spinal cord barrier and limits oxidative stress and white matter damage in the acutely injured murine spinal cord. J Cereb Blood Flow Metab 2007;27(5):1010-21.

Hsu JY, Bourguignon LY, Adams CM, Peyrollier K, Zhang H, Fandel T, Cun CL, Werb Z, Noble-Haeusslein LJ. Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord. J Neurosci 2008;28(50):13467-77.

Tsuru-Aoyagi K, Potts MB, Trivedi A, Pfankuch T, Raber J, Wendland M, Claus CP, Koh SE, Ferriero D, Noble-Haeusslein LJ. Glutathione peroxidase activity modulates recovery in the injured immature brain. Ann Neurol 2009;65(5):540-9.

Yoneyama-Sarnecky T, Olivas AD, Azari S, Ferriero DM, Manvelyan HM, Noble-Haeusslein LJ. Heme oxygenase-2 modulates early pathogenesis after traumatic injury to the immature brain. Dev Neurosci 2010;32(1):81-90.

Mao H, Jin X, Zhang L, Yang K, Igarashi, T, Noble-Haeusslein LJ, and King A.  Finite element analysis of controlled cortical impact injury- Investigation of intracranial tissue biomechanics. J Neuotrauma 2010; 27(5):877-88.

Claus C, Tsuru-Aoyagi K, Adwanikar H, Walker B, Whetstone W, Noble-Haeusslein LJ.  Age is a determinant of the inflammatory response and loss of cortical volume after traumatic brain injury. Dev Neuroscience. 2010. [Epub ahead of print]

Selected reviews:

Potts MB, Koh SE, Whetstone WD, Walker BA, Yoneyama T, Claus CP, Manvelyan HM, Noble-Haeusslein LJ. Traumatic injury to the immature brain: inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRx 2006;3(2):143-53.

Potts MB, Adwanikar H, Noble-Haeusslein LJ. Models of traumatic cerebellar injury. Cerebellum 2009;8(3):211-21.

Zhang H, Adwanikar H, Werb Z, Noble-Haeusslein LJ. Matrix metalloproteinases and neurotrauma: evolving roles in injury and reparative processes. Neuroscientist 2010;16(2):156-70.

Cernak I, Noble-Haeusslein LJ. Traumatic brain injury: an overview of pathobiology with emphasis on military populations. J Cereb Blood Flow Metab 2010;30(2):255-66

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Linda Noble, Ph.D.



Email

linda.noble@ucsf.edu

Phone

415-476-4850
415-502-2667

Office Address

UCSF MC 0520
513 Parnassus Ave, room HSE-722
San Francisco, CA 94143

Other Websites

Biomedical Sciences Graduate Program

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research

Neurological Surgery