Glucocorticoids and Apoptosis of Cerebellar Neural Progenitor Cells

描述（由申请人提供）：本申请要求支持与主要研究者最近发现糖皮质激素（例如，地塞米松）触发小脑外颗粒层中的神经祖细胞（NPC）的凋亡。 糖皮质激素仅在小脑NPC细胞分裂和细分的短暂时期内诱导这些细胞死亡，以产生随后将成为内部颗粒层中的颗粒细胞的神经元，并可能成为分子层中的中间神经元。 在啮齿类动物中，这一时期发生在出生后4-10天之间。 在人类中，相应的时期将从受孕后的第20周到第45周持续。 在小脑神经发生完成后，NPC通过凋亡被去除。 这些NPC用来决定何时开始通过凋亡杀死自己的信号是未知的。 确定信号可能是什么对发育神经生物学具有重要意义。 事实上，11？- 羟类固醇脱氢酶2型，一种只分解内源性糖皮质激素的酶，在神经发生期结束时，当NPC发生凋亡时，从小脑的外部颗粒层消失，表明内源性糖皮质激素可能是天然信号。 临床上，外源性糖皮质激素（例如，地塞米松，β-地塞米松）给予妊娠32周前分娩风险高的母亲，以诱导胎儿肺成熟。 此外，出生后的早产儿接受皮质类固醇2-42天，以预防或治疗慢性肺部疾病。 来自临床试验的随访数据表明，暴露于糖皮质激素的婴儿除了发育迟缓和较小的大脑和身体外，还有运动技能，运动协调和视觉运动整合的障碍。 这些数据引起了对人类婴儿糖皮质激素暴露的相对安全性的关注。 在本申请的具体目标1中提出的组织学工作试图确定糖皮质激素通过激活糖皮质激素受体产生细胞凋亡，并且内源性糖皮质激素比合成糖皮质激素更不可能产生这种毒性。 然后，将在具体目标2中研究单剂量糖皮质激素对小脑神经元数量以及运动和协调任务的长期影响。 拟议的研究结果可以为哪些糖皮质激素对人体毒性较小提供直接指导。 此外，这些发现将作为进行未来研究的基础，旨在更全面地了解细胞何时发生凋亡的基本生物学决定，并找到可能更有效地预防这种药物诱导的凋亡的治疗方法。

DESCRIPTION (provided by applicant): This application requests support for studies pertaining to the principal investigator's recent finding that glucocorticoids (e.g., dexamethasone) trigger apoptosis in neural progenitor cells (NPCs) in the external granule layer of the cerebellum. Glucocorticoids induce the death of cerebellar NPCs only during a brief period when these cells are dividing and subdividing in order to produce neurons that will subsequently become granule cells in the internal granule layer and, possibly, interneurons in the molecular layer. In rodents this period occurs between postnatal days 4-10. In humans the corresponding period would last from the 20th week to the 45th week post conception. After cerebellar neurogenesis has been accomplished, the NPCs are removed by apoptosis. The signal that these NPCs use to decide when to begin to kill themselves by apoptosis is unknown. Determining what the signal might be has important implications for developmental neurobiology. The fact that 11¿-hydroxysteroid dehydrogenase type 2, an enzyme that breaks down only endogenous glucocorticoids, disappears from the external granule layer of the cerebellum at the end of neurogenesis period, when NPCs undergo apoptosis, suggests that endogenous glucocorticoids might be the natural signal. Clinically, exogenous glucocorticoids (e.g., dexamethasone, betamethasone) are given to mothers, who are at high risk of giving birth prior to 32 weeks gestation, in order to induce maturation of the fetal lungs. In addition postnatal premature infants receive corticosteroids for 2-42 days either to prevent or treat chronic lung disease. Follow-up data from clinical trials suggest that infants exposed to glucocorticoids in addition to having developmental delays and smaller brains and bodies, have impairments in motor skills, motor coordination, and visualmotor integration. These data have raised concern about the relative safety of glucocorticoid exposure in the human infants. The histological work proposed in Specific Aim 1 of this application seeks to determine that glucocorticoids produce apoptosis by activating glucocorticoid receptors and that endogenous glucocorticoids are less likely to produce this toxicity than synthetic ones. Then the long-term effect of a single dose of glucocorticoids on cerebellar neuronal numbers and on motor and coordination tasks will be studied in Specific Aim 2. Results of the proposed studies could provide immediate guidance on which glucocorticoids might be less toxic in humans. In addition the findings will serve as a basis for conducting future studies aimed at more fully understanding the basic biology underlying decisions about when cells undergo apoptosis, and on finding treatments that might be more effective in preventing this drug-induced apoptosis.