Regulation of Neuronal Mitosis

神经元有丝分裂的调节

基本信息

批准号：
7777051
负责人：
Emanuel Murray DiCicco-Bloom
金额：
$ 8.65万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7777051
关键词：
Acute Affect Age Animal Behavior Animal Model Animals Anticonvulsants Anxiety Apoptosis Astrocytes Behavior Behavioral Benefits and Risks Binding Birth Brain Brain Diseases Brain region Brain-Derived Neurotrophic Factor Bromodeoxyuridine CDKN1C gene Carrier Proteins Cell Count Cell Cycle Cell Cycle Regulation Cell Death Cell Line Cell Lineage Cell Proliferation Cells Cerebral cortex Cerebrum Cessation of life Childhood Cognition Collaborations Complex Cues Cyclin D1 Cyclin E Cyclin-Dependent Kinase Inhibitor Cyclins DNA biosynthesis Development Differentiation Antigens Discrimination Disease Dose Drug Exposure Embryo Environmental Risk Factor Epilepsy Exhibits Exploratory Behavior Exposure to Family Female Female of child bearing age Fetus Fibroblast Growth Factor Fibroblast Growth Factor 2 Fibroblasts First Pregnancy Trimester Forebrain Development Generations Glial Fibrillary Acidic Protein Glutamate Transporter Growth Hand Heart Human Human Development IGF1 gene In Situ Nick-End Labeling In Vitro Instruction Intervention Knowledge Learning Limb structure Locomotion Measures Mental disorders Migraine Mitogens Mitosis Modeling Modification Molecular Mood Disorders Mothers Mus Nervous system structure Neuroglia Neuronal Differentiation Neurons Neuropeptides Newborn Infant Pathway interactions Perinatal Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Play Positioning Attribute Postdoctoral Fellow Production Prophylactic treatment Prosencephalon Publishing Rattus Reaction Time Regulation Role Schizophrenia Second Messenger Systems Signal Pathway Signal Transduction Social Behavior Social Interaction Specialist Specificity Spinal Cord Spinal Dysraphism Stimulus Syndrome System Teratogens Therapeutic Therapeutic Effect Third Pregnancy Trimester Thymidine Treatment Efficacy Treatment Protocols Valproic Acid Ventricular Vimentin autism spectrum disorder base brain cell brain size caspase-3 cell type depression effective therapy extracellular fetal gliogenesis in vivo insight male malformation member memory process morris water maze nestin protein neurogenesis neuron development neuropsychiatry offspring oncoprotein p21 pituitary adenylate cyclase activating polypeptide postnatal pregnant prenatal prevent response second messenger sensor social

项目摘要

Generation ofthe correct numbers and types of neural cells, including neurons and astrocytes, is fundamental to normal brain development and function. Conversely, alterations in brain cell composition, especially forebrain, are considered substrate of mature mental disorders with developmental origins, such as schizophrenia, depression and autism spectrum disorder. Previously we defined positive and negative extracellular signals, including FGF, IGF1 and PACAP, and intrinsic cell cycle mechanisms that regulate neurogenesis in cerebral cortex. Using this model, we are defining mechanisms by which the neurotherapeutic valproic acid (VPA), routinely administered to women of childbearing age, affects neuro/gliogenesis, because it is a teratogen that causes malformations and contributes to neuropsychiatric disorders. We hypothesize that VPA disrupts normal brain development by differentially regulating generation of neurons and glia, altering BDNF signaling and disturbing subsequent behavioral function. We find that VPA stimulates neurogenesis in culture and in embryos via cell cycle machinery, differentially regulates gliogenesis and alters BDNF signaling. Our Aims are: 1. Define effects of VPA on prenatal cortical neurogenesis and cell cycle machinery; 2. Define VPA effects on proliferation and differentiation of astrocytes; 3. Define effects of maternal VPA treatment on behavior of offspring during development and maturity. Studies will examine DNA synthesis, proliferation, differentiation, cell death, cell cycle western/RT- PCR and kinase analyses, cell composition by stereology, in culture and/or in developing pre- and postnatal animals, as well as assessments of exploratory behavior, social and anxiety measures and learning and memory processes. By defining cell type specific effects of VPA on intracellular signaling and cell cycle machinery, and characterizing consequences for brain cell composition and animal behavior during development, we may provide fundamental knowledge to effectively evaluate the benefits and risks of drug therapy, and identify pathways where intervention may counter detrimental effects of drug exposure. RELEVANCE (See instructions): Valproic acid (VPA) is routinely administered to women of childbearing age as therapy for epilepsy, mood disorders and migraine prophylaxis, raising concerns about contributions to developmental brain disorders. By defining effects on intracellular signaling, cell cycle machinery, brain cell composition and behavior, we may provide insights to evaluate VPA risks and benefits and identify pathways to prevent detrimental effects.

神经细胞的正确数量和类型的产生，包括神经元和星形胶质细胞，是正常大脑发育和功能的基础。相反，脑细胞组成的改变，尤其是前脑，被认为是具有发育起源的成熟精神障碍的底物，作为精神分裂症，抑郁和自闭症谱系障碍。以前我们定义了正面和负面细胞外信号，包括FGF，IGF1和PACAP，以及调节的内在细胞周期机制脑皮质中的神经发生。使用此模型，我们正在定义机制神经疗法丙戊酸（VPA）常规给予生育年龄的妇女神经/神经胶质发生，因为它是导致畸形并有助于神经精神病的致病原疾病。我们假设VPA通过差异调节来破坏正常的大脑发育神经元和神经胶质的产生，改变了BDNF信号传导和随后的行为功能。我们发现VPA通过细胞周期机制刺激培养和胚胎中的神经发生，差异调节神经胶质发生并改变BDNF信号传导。我们的目标是：1。定义VPA对产前皮质的影响神经发生和细胞周期机制； 2。定义VPA对增生和分化的影响星形胶质细胞； 3。定义母体VPA处理对发展过程中后代行为的影响到期。研究将检查DNA合成，增殖，分化，细胞死亡，细胞周期西部/RT- PCR和激酶分析，在培养和/或发展产后和产后的培养和/或中的细胞组成动物以及探索行为，社会和焦虑措施和学习的评估以及内存过程。通过定义VPA对细胞内信号传导和细胞周期的特异性影响机械以及表征对脑细胞组成和动物行为的后果开发，我们可以提供基本知识来有效评估毒品的益处和风险治疗，并确定干预措施可能应对药物暴露的有害影响的途径。相关性（请参阅说明）：丙戊酸（VPA）常规给予育龄女性作为癫痫病的治疗疾病和偏头痛预防，引起对发育性脑疾病的贡献的担忧。通过定义对细胞内信号，细胞周期机械，脑细胞组成和行为的影响，我们可能会提供见解以评估VPA风险和收益，并确定防止有害影响的途径。