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（如地塞米松）触发小脑外颗粒层神经祖细胞（npc）凋亡有关的研究。糖皮质激素仅在这些细胞分裂和再分裂以产生神经元的短暂时期内诱导小脑npc死亡，这些神经元随后将成为内部颗粒层的颗粒细胞，并可能成为分子层的中间神经元。在啮齿动物中，这一时期发生在出生后4-10天。在人类中，相应的时期将从受孕后的第20周持续到第45周。小脑神经发生完成后，npc通过细胞凋亡被清除。这些npc用来决定何时开始通过细胞凋亡来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。11 -羟基类固醇脱氢酶2型，一种只分解内源性糖皮质激素的酶，在神经发生末期，当npc发生凋亡时，从小脑外颗粒层消失，这一事实表明内源性糖皮质激素可能是自然信号。临床上，外源性糖皮质激素（如地塞米松、倍他米松）用于妊娠32周前分娩风险高的母亲，以诱导胎儿肺成熟。此外，产后早产儿接受2-42天的皮质类固醇治疗，以预防或治疗慢性肺病。临床试验的后续数据表明，接触糖皮质激素的婴儿除了发育迟缓、大脑和身体更小之外，还会在运动技能、运动协调和视觉运动整合方面受到损害。这些数据引起了人们对人类婴儿接触糖皮质激素的相对安全性的关注。本申请的Specific Aim 1中提出的组织学工作旨在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，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将在Specific Aim 2中进行研究。拟议的研究结果可以为哪种糖皮质激素对人体的毒性更小提供直接指导。此外，这些发现将为开展未来的研究奠定基础，旨在更全面地了解细胞何时发生凋亡的基本生物学决定，并寻找可能更有效地预防这种药物诱导的细胞凋亡的治疗方法。

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.