Graduate Studies Faculty
Stephen A. Back, M.D., Ph.D.
Programs:Neuroscience Graduate Program
Research Interests:glia development oligodendrocyte cell death apoptosis hypoxia ischemia neuroimaging MRI neurovascular unit extracellular matrix human neuropathology neurophysiology neuroanatomy immunohistochemistry stereology ethanol cortical development dementia Alzheimer's disease Vascular cognitive impairment Neuronal Maturation, Neurobiology of Disease » Click here for more about Dr. Back's research » PubMed Listing
Preceptor RotationsDr. Back has not indicated availability for preceptor rotations at this time.
Faculty MentorshipDr. Back is available as a mentor for 2016-2017.
Summary of Research Interests
My laboratory works at the interface between developmental neurobiology and pediatric neurology. Our major objective is to define cellular and molecular mechanisms related to perinatal white matter injury (PWMI). White matter injury is the major form of brain injury in the premature infant and underlies the development of the spastic motor deficits of cerebral palsy as well as cognitive impairment. Since death of oligodendrocyte (OL) progenitors could explain the impaired myelination that characterizes chronic white matter injury, we are taking several complementary approaches to test the hypothesis that the cellular basis for this injury is a maturation-dependent susceptibility of OL progenitors to death from hypoxia-ischemia.One focus of our work is human neuropathology studies that employ OL lineage-specific markers to immunohistochemically define events related to normal human OL lineage progression and myelination. We have, for example, defined the stages in the human OL lineage that are putative targets in white matter lesions. We have identified that late OL progenitors almost exclusively populate the white matter throughout the period in brain development when the risk for white matter injury is greatest (J. Neuroscience, 2001). Recent studies have identified a particular susceptibility of the OL lineage to oxidative damage in early human white matter lesions identified in autopsy brains from premature infants (Annals of Neurology 2005).
Second, we are defining mechanisms of susceptibility of late OL progenitors to oxidative stress in vitro, a well-established sequela of hypoxia-ischemia. We have shown that late OL progenitors are markedly more susceptible than mature OLs to death mediated by an oxidative stress pathway in which glutathione depletion triggers free radical toxicity in late OL progenitors that is blocked by antioxidants (J. Neuroscience, 1998). We have developed a novel neural stem cell-based tissue culture system to generate large numbers of highly enriched OL progenitors. With this system we have succeeded in generating large numbers of essentially astrocyte-free cultures of OL progenitors and mature OLs. This system is ideal for generating the large numbers of OL lineage cells needed for gene profiling and signal transduction studies (J. Neurochemistry, 2007)
Third, we are developing small and large animal models of perinatal white matter injury in order to determine whether targeted death of preOLs occurs from hypoxia ischemia in vivo. We first developed a neonatal rat model of hypoxia-ischemia (H-I) that causes white matter injury and neuronal apoptosis. We found that of late OL progenitors (preOLs) are highly susceptible to death from H-I in vivo whereas earlier and later OL lineage stages are much more resistant to H-I (J. Neuroscience, 2002). This finding suggests an explanation for the developmental specificity of PVL based upon the predominance of preOLs in preterm human fetal white matter. We extended these observations by developing a 0.65 gestation fetal sheep model of in utero global cerebral ischemia. This model generates graded cerebral white matter injury that reproduces the spectrum of pathology associated with PWMI. This model allows considerable integration of molecular, histological, and physiological approaches. A recent major advance is the ability to define in utero the regional heterogeneity of fetal cerebral blood flow through the application of fluorescently-labeled microspheres. Through this approach, we are generating three dimensional reconstructions of blood flow in fetal brain under basal conditions and conditions of ischemia-reperfusion. Using this approach we reported the surprising finding that cerebral ischemia is necessary but not sufficient to generate periventricular white matter injury (J.Neuroscience, 2006). Rather, the spatial heterogeneity of injury is accounted for by the distribution of susceptible preOLs.
Our long term objectives are to understand the mechanisms that predispose OL progenitors to death from hypoxia-ischemia, to establish the relationship between OL death, the genesis of myelination disturbances in the developing white matter and mechanisms of secondary cortical maturation failure. Toward this end we are currently defining the role of the extracellular matrix in the pathogenesis of chronic brain injury. Glial scarring in the form of chronic reactive gliosis is a central feature of chronic PWMI. Recently we identified that one component of the matrix, a high molecular weight astrocytes-derived form of hyaluonic acid reversibly blocks the maturation of oligodendrocyte progenitors in vitro. In vivo, this form of HA causes arrested remyelination after chemical injury to the myelin (Nature Medicine, 2005). Such studies suggest a new translational approach for intervention in chronic PWMI directed at degradation of components of the extracellular matrix that inhibit remyelination.
Back, S.A., Tuohy, T.M.F., H. Chen, N. Wallingford, A. Craig, J. Struve, N. Luo, F. Banine, Y. Liu, A. Chang, B.D. Trapp, B.F. Bebo, Jr., M.S. Rao, L.S. Sherman. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation, Nature Medicine 9:966-972, 2005.
Back,S.A., N.L. Luo N.L., R.A. Mallinson, J.P. O'Malley, L.D. Wallen, B. Frei, J.D. Morrow, C.K. Petito, C.T. Roberts Jr., G.H. Murdoch, T.J. Montine. Human preterm cerebral white matter is selectively vulnerable to oxidative damage identified by F2-isoprostanes, Annals of Neurology 58:108-120, 2005.