Noble Laboratory

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 are being used to define those substrates the govern recovery with the long-term goal of developing therapeutics that are specifically tailored for patients with brain and spinal cord injuries.

Current Research Projects

Bone-marrow-derived macrophages (F4/80 , green) show typical uptake of FluoSpheres (blue, left figure). This function is maintained when cells are labeled with Qdots (red, right panel). Image courtesy of Haoqian Zhang, PhD.Spinal cord injury
Matrix metalloproteinases (MMPs)
We have shown that MMPs, a family of zinc and calcium requiring endopeptidases, play differing roles in the acutely injured spinal cord and during wound healing. Ongoing studies, using both pharmacologic and genetic approaches, examine the cellular and molecular interactions between MMPs and leukocyte trafficking, angiogenesis, and remodeling of the extracellular matrix.  Click on Image.

L-selectin, a leukocyte cell adhesion receptor, functions in a variety of leukocyte-endothelial interactions, which underlie normal and inflammatory leukocyte trafficking. We are using genetic approaches in combination with the generation of chimeric animals to study the role of this receptor in posttraumatic demyelination.

Stem cell-directed recovery
Ongoing studies address the functional integration of precursors, derived from the medial ganglionic eminence, in the injured rodent spinal cord, with the goal of improving bladder control and reducing involuntary muscle spasms.

Appearance of the immature brain after traumatic injury at postnatal day 21. There is a prominent accumulation of macrophages (FITC labeled lectin) within the injured hemisphere at 7 days post injury.Traumatic injury to the developing brain
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. Our current studies focus on antioxidant reserves as determinants of structural and cognitive recovery after injury, using state-of-the art high resolution MRI together with comprehensive anatomical, behavioral and molecular assays. Click on Image.

Experimental findings reveal emerging cognitive deficits after traumatic injury to the developing brain that coincides with prolonged trafficking of granulocytes into cortical and subcortical structures. Current studies focus on leukocyte interactions at the level of the neurovascular unit, with emphasis on matrix-metalloproteinase-directed barrier dysfunction and irreversible neuronal injury.