Mechanisms and consequences of CNS aneuploidies altered by fetal ethanol exposure

胎儿乙醇暴露改变中枢神经系统非整倍体的机制和后果

• 批准号: 8700252
• 负责人: JEROLD CHUN
• 金额: $ 36.76万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700252
• 关键词: Adult; Affect; Aneuploid Cells; Aneuploidy; Behavior; Behavioral; Birth; Brain; Cell Death; Cell Proliferation; Cells; Cerebral cortex; Chromosomal Gain; Chromosomes; Congenital Abnormality; Data; Date of birth; Defect; Disease; Dose; Down Syndrome; Elements; Embryo; Emotions; Engineering; Ethanol; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fluorescent in Situ Hybridization; Foundations; Functional disorder; Generations; Genome; In Situ; Life; Location; Malignant Neoplasms; Mental Retardation; Mitotic; Molecular; Mus; Neuraxis; Neurons; Perinatal Exposure; Physiological; Population; Reporter; Spectral Karyotyping; Stereotyping; System; Testing; Time; Vertebrates; alcohol exposure; autosome; brain cell; cell type; fetal; in vivo; nerve stem cell; neurobiological mechanism; neurodevelopment; neurogenesis; neuron development; novel; postnatal; prenatal; prenatal exposure; public health relevance; relating to nervous system; research study; response; stem

DESCRIPTION (provided by applicant): In utero exposure to alcohol can have major deleterious effects as documented for "fetal alcohol syndrome (FAS)" and more recently and broadly as "fetal alcohol spectrum disorders (FASD)." These disorders are associated with a range of debilitating neurodevelopmental and psychiatric problems after birth. Myriad molecular and cellular defects have been associated with fetal brain exposure to ethanol, which generally lack common, underlying mechanisms. This proposal will examine a newly identified, somatic change in the genomes of central nervous system (CNS) cells produced by fetal ethanol exposure that could help to provide a common mechanistic foundation: mosaic aneuploidies. These cells show somatically produced chromosomal gains and/or losses, constituting an inherent, if surprising element of normal brain organization. Constitutive aneuploidies (where all cells have the same form of aneuploidy) have clear consequences for cellular dysfunction in cancers, and deleterious behavioral consequences as observed in Down Syndrome, suggesting that deviations from the normal mosaic aneuploidy states could contribute to the range of neural deficits seen in FASD. Here, we will test the hypothesis that identifiable changes in neural mosaic aneuploidies represent a common endpoint of prenatal exposure to alcohol. Three aims will be pursued over the next 5 years. Aim 1 will identify effects of fetal alcohol exposure that alter neural progenitor cell (NPC) aneuploidies after embryonic exposure ex vivo. Aim 2 will determine cell fate and functional consequences of alcohol exposure to aneuploid & aneusomic NPC populations during development, and neurons in adult cortical cell populations. Aim 3 will determine neuronal and non-neuronal identities and distributions of specific aneusomies produced by fetal alcohol exposure using a novel in vivo reporter system. Completion of these Aims could provide a new framework for understanding and therapeutically approaching FASD.

描述（由申请人提供）：在子宫内暴露于酒精时，可能具有“胎儿酒精综合征（FAS）”的重大有害作用，而最近又广泛地称为“胎儿酒精谱系障碍（FASD）”。这些疾病与出生后的一系列令人衰弱的神经发育和精神病问题有关。无数分子和细胞缺陷与胎儿脑暴露于乙醇相关，乙醇通常缺乏常见的潜在机制。该提案将检查胎儿乙醇暴露产生的中枢神经系统（CNS）细胞的新鉴定的躯体变化，这可以帮助提供共同的机械基础：镶嵌性动态倍增性。这些细胞显示出体面产生的染色体增益和/或损失，构成了正常脑组织的固有元素，甚至令人惊讶的元素。组成型的非整倍性（所有细胞都具有相同形式的非整倍性）对癌症中细胞功能障碍有明显的后果，而在唐氏综合征中观察到的有害行为后果，表明与正常镶嵌性动态态的偏差可能导致Fasd中看到的神经缺陷范围。在这里，我们将检验以下假设：神经镶嵌性脑倍倍体的可识别变化代表了产前暴露于酒精的常见终点。未来5年将追求三个目标。 AIM 1将确定胎儿暴露于胚胎暴露后改变神经祖细胞（NPC）非整倍性的胎儿酒精暴露的影响。 AIM 2将确定在发育过程中酒精暴露于非整倍体和Aneusomic NPC种群的细胞命运和功能后果，以及成人皮质细胞群体中的神经元。 AIM 3将确定使用新型的体内报告基因系统，确定胎儿酒精暴露产生的特定障碍物的神经元和非神经元身份。这些目标的完成可以为理解和治疗接近FASD提供一个新的框架。