CNS PRECURSOR CELL DYSFUNCTION IN DEVELOPMENTAL MALADIES

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Many different physiological insults to the developing child result in long-lasting neurological impairment associated with a failure of myelination and/or destruction of existing myelin and a subsequent inability to repair this damage. Such impairment is associated, for example, with deficiencies in thyroid hormone, iron with inadequate nutrition, with fetal exposure to alcohol or cocaine, as a result of hypoxic episodes or in association with radiotherapy or chemotherapy. We propose that the underlying cellular basis for many childhood disorders of neurological development is disruption of specific steps in the development of the precursor cells that give rise to the differentiated cell types of the central nervous system (CNS). Consistent with this hypothesis, we have discovered that specific steps in development of the myelin-forming oligodendrocytes of the CNS are disrupted in the two specific instances of thyroid hormone and iron deficiency. Initially, we will carry out in vitro and in vivo studies on hypothyroidism, as a well-defined model of hormonal and nutritional deficiency disorders. These studies will provide a detailed map of the stages of precursor cell development vulnerable to deficiency of thyroid hormone. To determine why hormonal replacement therapy applied at too late a stage does not promote repair of CNS damage, we next will transplant defined stem cell and precursor cell populations into the CNS of animals that have been hypothyroid throughout development and examine the ability of these cells to contribute to tissue repair. These experiments will provide insight into whether the failure to reconstitute normal development is due solely to an absence of appropriate precursor cells, or also is due to the CNS becoming refractory to repair. Complementary to this cellular biological analysis, we also will determine whether intracellular redox modulation is a critical component of the mechanism by which thyroid hormone exerts its effects on all the CNS precursor cells regulated by this hormone. In addition, we will extend preliminary observations indicating that the very different disorder of iron deficiency may also work in part through alteration of intracellular redox state. By asking whether different syndromes exert their effect through overlapping mechanisms, these studies may provide important clues to potential new therapeutic approaches to the treatment of hormonal and nutritional deficiency disorders. In sum, this research program will identify both cellular and biochemical mechanisms that explain the biology of critical developmental periods and may lead to the identification of therapeutic approaches that can enhance repair in multiple deficiency syndromes.