CNS PRECURSOR CELL DYSFUNCTION IN DEVELOPMENTAL MALADIES

对发育中的儿童的许多不同的生理损伤导致与髓鞘形成失败和/或现有髓鞘的破坏以及随后无法修复这种损伤相关的长期神经损伤。 这种损害与例如甲状腺激素、铁缺乏、营养不足、胎儿暴露于酒精或可卡因、缺氧发作或放疗或化疗有关。我们提出，许多儿童期神经发育障碍的潜在细胞基础是前体细胞发育中特定步骤的破坏，这些前体细胞产生中枢神经系统（CNS）的分化细胞类型。 与这一假设相一致，我们发现，在甲状腺激素和铁缺乏的两个特定情况下，CNS髓鞘形成少突胶质细胞发育的特定步骤被破坏。最初，我们将进行甲状腺功能减退症的体外和体内研究，作为激素和营养缺乏症的明确模型。 这些研究将提供一个详细的地图，前体细胞的发展阶段，容易缺乏甲状腺激素。 为了确定为什么激素替代疗法在太晚的阶段应用不能促进CNS损伤的修复，我们接下来将确定的干细胞和前体细胞群移植到在整个发育过程中甲状腺功能减退的动物的CNS中，并检查这些细胞促进组织修复的能力。 这些实验将提供洞察重建正常发育的失败是否仅仅是由于缺乏适当的前体细胞，或者也是由于CNS变得难以修复。 作为对细胞生物学分析的补充，我们还将确定细胞内氧化还原调节是否是甲状腺激素对受该激素调节的所有CNS前体细胞发挥作用的机制的关键组成部分。 此外，我们将扩展初步观察表明，非常不同的铁缺乏症也可能通过改变细胞内氧化还原状态的部分工作。 通过询问不同的综合征是否通过重叠机制发挥作用，这些研究可能为治疗激素和营养缺乏症的潜在新治疗方法提供重要线索。总之，这项研究计划将确定细胞和生化机制，解释关键发育期的生物学，并可能导致识别治疗方法，可以增强修复多种缺陷综合征。

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.