Mechanisms and consequences of CNS aneuploidies altered by fetal ethanol exposure

描述（由申请人提供）：在子宫内接触酒精会产生严重的有害影响，如文献记载的“胎儿酒精综合征（FAS）”和最近更广泛的“胎儿酒精谱系障碍（FASD）”。这些疾病与出生后一系列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暴露于乙醇有关，通常缺乏共同的潜在机制。本研究将研究胎儿乙醇暴露产生的中枢神经系统（CNS）细胞基因组中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：马赛克非整倍体。这些细胞显示出体细胞产生的染色体增益和/或损失，构成正常大脑组织的固有元素，如果令人惊讶的话。组成性非整倍体（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有明显的影响，并且在唐氏综合症中观察到有害的行为后果，这表明偏离正常的嵌合非整倍体状态可能导致FASD中所见的神经缺陷范围。在这里，我们将验证神经马赛克非整倍体的可识别变化代表产前暴露于酒精的共同终点的假设。未来5年将实现三个目标。目的1将确定胎儿酒精暴露在体外暴露后改变神经祖细胞（NPC）非整倍体的影响。目的2将确定酒精暴露对发育期间非整倍体和无染色体NPC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影响。目的3将使用一种新的体内报告系统确定胎儿酒精暴露产生的特异性动脉瘤的神经元和非神经元身份和分布。这些目标的完成可以为理解和治疗FASD提供新的框架。

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.