Glucocorticoids and Apoptosis of Cerebellar Neural Progenitor Cells

糖皮质激素与小脑神经祖细胞的凋亡

• 批准号: 7240306
• 负责人: NURI B FARBER
• 金额: $ 7.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7240306
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Adrenal Cortex Hormones; Adult; Apoptosis; Behavior; Betamethasone; Biology; Birth; Brain; Cells; Cerebellum; Cessation of life; Chronic lung disease; Clinical Trials; Conceptions; Corticosterone; Cytoplasmic Granules; Daily; Data; Development; Developmental Delay Disorders; Dexamethasone; Dose; Enzymes; Fetal Lung; Future; GABA Agents; Glucocorticoid Receptor; Glucocorticoids; Human; Hydroxysteroid Dehydrogenases; Impairment; Infant; Interneurons; Long-Term Effects; Mediator of activation protein; Mothers; Motor; Motor Skills; N-Methylaspartate; Neuraxis; Neurons; Numbers; Pharmaceutical Preparations; Pregnancy; Premature Infant; Principal Investigator; Property; Relative (related person); Request for Applications; Risk; Rodent; Safety; Signal Transduction; Solvents; Structure of molecular layer of cerebellar cortex; Toxic effect; Week; Work; base; day; developmental neurobiology; follow-up; granule cell; improved; insight; killings; nerve stem cell; neurodevelopment; neurogenesis; neurotoxic; postnatal; prevent; visual-motor integration

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.

描述（由申请人提供）：本申请请求支持与主要研究者最近发现的糖皮质激素（例如地塞米松）触发小脑外颗粒层神经祖细胞（NPC）细胞凋亡相关的研究。小脑 NPC 仅在这些细胞分裂和细分以产生神经元的短暂时期内，这些神经元随后会变成在啮齿类动物中，这一时期发生在出生后 4-10 天之间，而在人类中，相应的时期将持续到受孕后第 20 周至第 45 周。完成后，NPC 通过细胞凋亡被清除，但这些 NPC 用于决定何时开始通过细胞凋亡杀死自己的信号尚不清楚，但确定该信号可能对发育具有重要意义。神经生物学的事实是11¿ -2型羟基类固醇脱氢酶是一种仅分解内源性糖皮质激素的酶，在神经发生期结束时，当NPC发生细胞凋亡时，会从小脑的外部颗粒层消失，这表明内源性糖皮质激素可能是临床上外源性糖皮质激素的自然信号。 （例如，地塞米松、倍他米松）给予高风险的母亲妊娠 32 周之前出生，以促进胎儿肺部成熟。此外，出生后的早产儿接受皮质类固醇治疗 2-42 天，以预防或治疗慢性肺部疾病。糖皮质激素除了导致发育迟缓、大脑和身体变小之外，还会损害运动技能、运动协调和视觉运动整合。这些数据引起了人们对糖皮质激素暴露的相对安全性的担忧。本申请的具体目标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。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影响将在具体目标 2 中进行研究。拟议研究的结果可以立即提供此外，这些发现将作为未来研究的基础，旨在更全面地了解有关细胞何时发生凋亡的基本生物学决定，并寻找可能更有效的治疗方法。防止这种药物诱导的细胞凋亡。