Response Signatures of Alcohol-Related Birth Defects

描述（由申请人提供）：孕妇在怀孕期间饮酒是一个重大的公共卫生问题。它影响了1%的婴儿，是导致智力迟钝的主要可预防原因。本项目探讨目标器官对产前酒精暴露的易感性机制。眼缺陷，如结肠瘤、小眼症和视神经发育不全是胎儿酒精综合征（FAS）的主要特征，反映了早期发育期间母亲接触酒精引起的病变。我们的假设表明，线粒体通过调用一个保守的发育可塑性检查点来对酒精诱导的氧化应激作出反应。检查点微调细胞重塑，但可能破坏应激条件下的形态发生重塑。该信号由线粒体Bzrp/TspO蛋白启动，这是一种氧感应信号发生器，并重塑信号网络。受体介导的细胞粘附途径最为敏感；因此，线粒体阻断了细胞核和细胞表面之间的分子调控信息流动。初步研究表明，C57BL/6J背景（B6J）是酒精性眼缺陷的高危人群，而C57BL/6N背景（B6N）的风险较低。PK11195是Bzrp/TspO的一种有效的药理学配体，可以保护B6J胚胎免受酒精相关的眼睛缺陷。特异性目的1将确定pk11195反应性眼缺陷的遗传易感性是否与妊娠小鼠胎儿酒精综合征的母体易感性有关。Specific Aim 2将通过基因（B6J, B6N），药理学（PK11195）和分子（反义）操作在全胚胎培养中建立Bzrp/TspO与酒精诱导的眼缺陷之间的因果关系。特异性Aim 3将识别在酒精诱导的眼缺陷发病过程中受体介导的细胞粘附系统改变的microRNA （miRNA）特征。具体目标4将维持“出生缺陷系统管理器”（BDSM）作为一个正在进行的生物信息学知识管理系统，以便对相关的发育和基因组数据进行二次分析。实现这些具体目标将有助于更好地了解与孕产妇饮酒相关的疾病风险，并可以推进对一般酒精相关出生缺陷的个体易感性的新诊断，特别是儿科眼科疾病。

DESCRIPTION (provided by applicant): Maternal alcohol use during pregnancy is a significant public health problem. It affects 1% infants and is the leading preventable cause of mental retardation. This project addresses the mechanisms of target organ susceptibility to prenatal alcohol exposure. Eye defects such as coloboma, microphthalmia and optic nerve hypoplasia are a cardinal feature of the Fetal Alcohol Syndrome (FAS) and reflect lesions induced by maternal alcohol exposure during early development. Our hypothesis states that mitochondria react to alcohol-induced oxidative stress by invoking a conserved checkpoint for developmental plasticity. The checkpoint fine-tunes cellular remodeling, but may disrupt morphogenetic remodeling under stressful conditions. The signal is started by the mitochondrial Bzrp/TspO protein, an oxygen-sensing signal generator and recasts signaling networks. Receptor-mediated cell adhesion pathways appear most sensitive; as such, mitochondria intercept the flow of molecular regulatory information between nucleus and cell surface. Preliminary studies show that the C57BL/6J background (B6J) is at high risk for alcohol-induced eye defects whereas the C57BL/6N background (B6N) carries a low risk. B6J embryos are protected from alcohol-related eye defects with PK11195, a potent pharmacological ligand for Bzrp/TspO. Specific Aim 1 will determine if genetic predisposition to PK11195-responsive eye defects is linked to the maternal disposition for Fetal Alcohol Syndrome in pregnant mice. Specific Aim 2 will establish a causal link between Bzrp/TspO and alcohol-induced eye defects using genetic (B6J, B6N), pharmacological (PK11195), and molecular (antisense) manipulation in whole embryo culture. Specific Aim 3 will identify microRNA (miRNA) signatures for receptor-mediated cell adhesion systems altered during the pathogenesis of alcohol-induced eye defects. Specific Aim 4 will sustain 'Birth Defects Systems Manager' (BDSM) as an ongoing bioinformatics-knowledge management system to enable secondary analysis of relevant developmental and genomic data. Achieving these Specific Aims will lead to a better understanding of the disease risks associated with maternal alcohol consumption and can advance new diagnostics for individual susceptibility to alcohol-related birth defects in general and pediatric ophthalmic disorders in particular.