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（由应用程序提供）：本应用要求支持与主要研究者最近的发现有关的研究，即糖皮质激素（例如，地塞米松）在小脑外颗粒层中神经元祖细胞（NPC）中触发了神经元祖细胞（NPC）的凋亡。糖皮质激素只有在这些细胞分裂和细分的短时间内诱导小脑NPC的死亡，以产生随后成为内部颗粒层中的颗粒细胞的神经元，并且可能在分子层中的中间神经元。在啮齿动物中，这一时期发生在产后第4-10天之间。在人类中，相应的时期将持续到第20周到概念后第45周。小脑神经发生后，通过凋亡去除NPC。这些NPC用来决定何时开始因细胞凋亡而自杀的信号尚不清楚。确定可能是什么信号对发育神经生物学具有重要意义。 11？ - 羟基甾体脱氢酶2型（仅分解的酶，仅内源性糖皮质激素，在神经发生期结束时小脑的外部颗粒层中消失，当NPCS发生凋亡时，这表明内源性glucoticoid可能是天然的。在临床上，为母亲提供了外源性糖皮质激素（例如，地塞米松，替他米松），为了诱导胎儿肺部的成熟，母亲有高风险，即在32周妊娠之前出生。另外，产后早产婴儿会接受2-42天的皮质类固醇，以预防或治疗慢性肺部疾病。来自临床试验的后续数据表明，除了发育延迟，大脑和身体较小的婴儿外，还暴露于糖皮质激素的婴儿，运动技能，运动协调和视觉速度积分的障碍。这些数据引起了人们对糖皮质激素暴露在人类婴儿中的相对安全性的关注。本应用的特定目的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凋亡，而内源性糖皮质激素比合成糖脂产生这种毒性的可能性较小。然后，单剂量的糖皮质激素对小脑神经元数以及运动和协调任务的长期影响将在特定的目标2中进行研究。拟议的研究的结果可以提供有关糖皮质激素在人类中可能毒性较小的立即指导。此外，这些发现将作为进行未来研究的基础，旨在更充分了解有关细胞凋亡何时凋亡的基本生物学的基本生物学，以及寻找可能在防止这种药物诱导的凋亡方面更有效的治疗方法。