Mechanisms and consequences of CNS aneuploidies altered by fetal ethanol exposure

描述(由申请人提供)：在子宫内接触酒精可能会有重大的有害影响，如文件所述的“胎儿酒精综合症(FAS)”，以及最近和更广泛的“胎儿酒精谱系障碍(FASD)”。这些障碍与出生后一系列使人衰弱的神经发育和精神问题有关。无数的分子和细胞缺陷与胎儿大脑接触乙醇有关，这通常缺乏共同的潜在机制。这项提议将研究由胎儿酒精暴露产生的中枢神经系统(CNS)细胞基因组中的一种新发现的体细胞变化，这可能有助于提供一个共同的机制基础：镶嵌非整倍体。这些细胞表现出体细胞产生的染色体的获得和/或丢失，构成了正常大脑组织的一个固有的、如果令人惊讶的元素。结构性非整倍体(其中所有细胞都具有相同形式的非整倍体)对癌症中的细胞功能障碍和唐氏综合征中观察到的有害行为后果具有明显的后果，这表明偏离正常的马赛克非整倍体状态可能会导致FASD出现神经缺陷的范围。在这里，我们将检验这一假设，即神经嵌合体非整倍体的可识别变化代表着产前接触酒精的共同终点。在接下来的5年里，我们将实现三个目标。目的1研究胎儿酒精暴露对体外胚胎暴露后神经祖细胞(NPC)非整倍体的影响。目的2将确定酒精暴露于发育过程中的非整倍体和新生鼻咽癌群体以及成年皮质细胞群体中的神经元的细胞命运和功能后果。目的3将使用一种新的体内报告系统来确定胎儿酒精暴露所产生的神经元和非神经元的身份和特定新生细胞的分布。这些目标的完成可以为理解和治疗FASD提供一个新的框架。

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.