NEUROGENESIS IN DISORDERS OF BRAIN DEVELOPMENT

大脑发育障碍中的神经发生

• 批准号: 6591415
• 负责人: BRUCE K KRUEGER
• 金额: $ 0.8万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-14 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6591415
• 关键词: Downs syndrome; biological signal transduction; blocking antibody; brain disorders; cAMP response element binding protein; calcium flux; cell cycle; cell growth regulation; cell proliferation; cerebral cortex; confocal scanning microscopy; developmental neurobiology; disease /disorder model; glutamate receptor; immunocytochemistry; laboratory mouse; nerve stem cell; neurogenesis; neurons; neurotransmitters; neurotrophic factors; phosphorylation; receptor expression; tissue /cell culture; trisomy

DESCRIPTION (adapted from applicant's abstract): The cause of mental retardation in Down syndrome (DS) is not understood but is thought to result, at least in part, from defective brain development during the embryonic period when neurons of the cerebral cortex are being generated. The trisomy 16 (Ts16) mouse shares a common genetic defect with DS and may be useful for studying the mechanisms underlying abnormal embryonic development of the cerebral cortex. Prenatal generation of postmitotic neurons in the Ts16 mouse cortex is delayed and subplate neurons are born concurrently with cortical plate neurons rather than preceding them as in the normal cortex. These abnormalities in the timing of Ts16 neurogenesis may lead to defective connectivity in the mature brain; similar defects during the prenatal development of the human brain may contribute to mental retardation in DS. Proliferation of neuroprogenitor cells (neuroblasts) and the decision of daughter cells to leave the cell cycle, which ultimately control the timing of neurogenesis, are regulated by neurotransmitters and growth factors such as glutamate and brain derived neurotrophic factor (BDNF). Ts16 neuroblasts fail to respond to glutamate and BDNF, raising the possibility that this signaling defect may underlie delayed neurogenesis in Ts16. The molecular basis for defects in the regulation of Ts16 neurogenesis will be studied in a) dissociated cell cultures of neuroblasts and b) organotypic slices from Ts16 and littermate euploid cortex. Both of these preparations enable not only the direct application of putative regulators of neurogenesis and of inhibitors of signaling pathways, but also direct measurement of proliferation, cell death and intracellular levels of Ca2+, a key modulator of proliferation, neuronal differentiation and migration. Experiments in organotypic slices will enable these processes to be analyzed in a structurally intact cortex and will allow the behavior of anatomically-distinct populations of neuroblasts and postmitotic neurons to be distinguished. The overall goals of this research project are to identify the signaling defects that lead to abnormal neurogenesis in the Ts16 mouse cerebral cortex and, at the same time, to determine the molecular signaling mechanisms underlying the control of neurogenesis in the normal brain.

描述（改编自申请人的摘要）：精神的原因 唐氏综合症（DS）的迟缓尚不清楚，但被认为是导致的， 至少部分是由于胚胎时期的大脑发育缺陷 当产生大脑皮质的神经元时。三体术16（TS16） 小鼠与DS共有常见的遗传缺陷，可能对研究 大脑皮层的异常胚胎发育的基础机制。 TS16小鼠皮层中有丝分裂神经元的产前产生延迟 和子板神经元同时出生于皮质板神经元而不是 与正常皮质中的前面一样。这些时机中的这些异常 TS16神经发生可能导致成熟大脑中的连通性缺陷。 人脑的产前发育期间的类似缺陷可能 在DS中有助于智力障碍。 神经元基因细胞的增殖（神经细胞）和决定的决定 子细胞离开细胞周期，最终控制 神经发生，受神经递质和生长因子（例如 谷氨酸和脑衍生的神经营养因子（BDNF）。 TS16神经细胞失败 响应谷氨酸和BDNF，提高了这种信号的可能性 缺陷可能是TS16中神经发生的延迟。 TS16神经发生调节中缺陷的分子基础将是 在A）神经细胞的分离细胞培养物和b）细胞型中进行了研究 TS16和同窝层的euploid Cortex的切片。这两个准备工作 不仅可以直接应用推定的神经发生调节剂 以及信号通路的抑制剂，但也直接测量 Ca2+的增殖，细胞死亡和细胞内水平，这是关键调节剂 增殖，神经元分化和迁移。实验 器官型切片将使这些过程在结构上进行分析 完整的皮质，将允许解剖学上的人群的行为 待区分的神经细胞和有丝分裂神经元的神经元。 该研究项目的总体目标是确定信号传导 导致TS16小鼠大脑皮层神经发生异常的缺陷 同时，确定分子信号传导机制 正常脑中神经发生的控制。