Linda J. Noble-Haeusslein Lab

Departments of Neurological Surgery and Physical Therapy and Rehabilitation Science

Laboratory  members

-Hita Adwanikar
Postdoctoral Fellow
Ph.D., Baylor College of Medicine
Blood-brain barrier dysfunction in the injured, developing brain

-Christine Cun
Research Associate
B.S., UC Berkeley
Gender effects on bladder integrity after spinal cord injury

-Joana D’Avila
Graduate Student
Federal University of Rio de Janeiro, Brazil
Oxidative stress in the injured, developing brain

-Thomas Fandel
Postdoctoral Fellow
M.D., University of Aachen, School of Medicine, Germany
Matrix metalloproteinases, posttraumatic inflammation, bladder function

-J.-Y. (Cliff) Hsu
Postdoctoral Fellow
Ph.D., St. Louis University
Matrix metalloproteinases as modifiers of the glial scar

-Joseph Kopshever
Graduate student
Physical Therapy and Rehabilitation Science, UCSF
Matrix metalloproteinases and wound healing in the injured brain

-Sang Mi Lee
Postdoctoral Fellow
Ph.D., Kangwon National University
L-selectin as a mediator of secondary damage in the injured spinal cord

-Alpa Trivedi
Assistant Researcher Molecular Biologist
Ph.D., Wright State University
Angiogenesis and spinal cord injury

-Katherine Yi
Graduate Student
Physical Therapy and Rehabilitation Science, UCSF
Macrophages as mediators of secondary damage in the injured spinal cord

-Haoqian Zhang
Postdoctoral Fellow
Ph.D., Nagoya University, Japan
Matrix metalloproteinases and wound healing in the injured spinal cord

Laboratory Mission Statement

Develop therapeutics for human clinical trials based upon their success in clinically relevant animals models of traumatic brain and spinal cord injury.

General overview

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 be 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. 

Areas of focus

  • Understanding mechanisms by which matrix metalloproteinases govern injury and repair processes.
  • Define the underlying factors contributing to cognitive decline in the injured, immature brain.
  • Develop mechanistic-based strategies to improve recovery of function after spinal cord injury and to rescue the cognitive decline seen in the injured, immature brain.

 

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.  In line with those objectives, we have recently developed chimeric animals to better understand the contribution of infiltrating leukocytes to secondary demyelination and bone marrow-derived cells to the revascularization process.

Brain injury. 
 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.

Funding and Contributors

Current:

NIH
Role of matrix metalloproteinases in spinal cord injury
Linda Noble, PI

NIH
Traumatic to developing brain- Injury and repair mechanisms
Linda Noble, PI

Oxnard Foundation
L-selectin as a modulator of demyelination in the traumatized spinal cord
Linda Noble, PI

NASA
Inflammation in the brain after particulate irradiation predisposes the hippocampus to a heightened vulnerability after a secondary insult
John Fike, PI

Department of Veterans Affairs
Reducing functional deficits following traumatic brain injury
Jialing Liu, PI

Past:

 NINDS,  NIH/SBIR, Roman Reed Foundation, Charles A. Dana Foundation, Sandler Foundation, UC Neurotrauma Grant, Biostar Program

Collaborators

Donna Ferriero, M.D.
John Fike, Ph.D.
Jialing Liu, Ph.D.
Jacob Raber, Ph.D.
Steven Rosen, Ph.D.
Kimberly Topp, Ph.D.
Henk Vreman, Ph.D.
Zena Werb, Ph.D.
William Whetstone, M.D.
Ron Wong, Ph.D.

Selected Publications

     Noble L J, Donovan F, Igarashi T, Goussev S, and Werb Z.  Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events.  Journal of Neuroscience,  22 7526-7535, 2002
     Chang E, Wong R, Vreman H, Galo E, Sharp F, Igarashi T, Stevenson D, and Noble-Haeusslein L J.  Heme oxygenase protects against lipid peroxidation-mediated cell loss and impaired motor recovery after traumatic brain injury.  Journal of Neuroscience. 23:3689-96, 2003.
     Whetstone W, Eisenberg M, Werb Z,and Noble-Haeusslein LJ.  The blood-spinal cord barrier after spinal cord injury:  Relation to revascularization and wound healing.  J of Neuroscience Research. 74:227-239, 2003.
Trivedi A, Igarashi T, Compagnone N, Fan X,  Hsu J,  Hall D, John C, and Noble-Haeusslein L.  Allogenic sertoli cells as a vehicle for the delivery of human neurotrophin-3 to the injured spinal cord. Experimental Neurology. 198:88-100, 2006.
     Hsu J-Y, McKeon R, Goussev S, Werb Z, Lee J-E, Trivedi A, and Noble-Haeusslein LJ.  Matrix metalloproteinase-2 deficiency results in wound healing events that limit functional recovery after spinal cord injury. Journal of Neuroscience. 26:9841-50, 2006.
     Pullela R, Raber J, Ferriero D, Claus C, Koh S, Yamauchi T, Rola  R, Fike J, and Noble-Haeusslein L J.  Traumatic injury to the developing brain results in progressive neuronal loss, hyperactivity, and delayed cognitive impairments. Developmental Neuroscience.  28:396-409, 2006.
     Lin Y, Potts, M and Noble-Haeusslein L J.  Heme Oxygenase-1 stabilizes the blood-spinal cord barrier and attenuates white matter damage in the acutely contused murine spinal cord.  Journal of Cerebral Blood Flow and Metabolism. 27:1010-1021, 2007.

Reviews:

          Chang E, Claus C, and Noble-Haeusslein L J.  Regulation of heme after traumatic brain injury:The role of heme oxygenases.  Journal of Cerebral Blood Flow and Metabolism.  27:169-75, 2005.
          Trivedi A, Olivas A, and Noble-Haeusslein LJ.  Inflammation and spinal cord injury:  Infiltrating leukocytes as determinants of injury and repair processes.  Clinical Neuroscience Research 6:283-292, 2006.
          Potts M, Koh, S-E, Whetstone W, Walker B, Yoneyama T, Claus C, Manvelyan H, and Noble-Haeusslein L J.  Traumatic injury to the developing brain:  Strategies to limit early damage and restore function.  NeuroRx. 3:143-53, 2006.