Response Signatures of Alcohol-Related Birth Defects

描述（由申请人提供）：母亲在怀孕期间饮酒是一个重大的公共卫生问题。它影响1%的婴儿，是智力迟钝的主要可预防原因。该项目旨在探讨产前酒精暴露对靶器官易感性的机制。眼睛缺陷，如缺损，小眼球和视神经发育不全是胎儿酒精综合征（FAS）的主要特征，反映了母亲在早期发育过程中暴露于酒精引起的病变。我们的假设指出，线粒体对酒精诱导的氧化应激反应调用一个保守的检查点发育可塑性。检查点微调细胞重塑，但可能会在压力条件下破坏形态发生重塑。该信号由线粒体Bzrp/TspO蛋白启动，这是一种氧传感信号发生器并重塑信号网络。受体介导的细胞粘附途径似乎最敏感;因此，线粒体拦截细胞核和细胞表面之间的分子调节信息流。初步研究表明，C57 BL/6 J背景（B6 J）对酒精诱导的眼睛缺陷具有高风险，而C57 BL/6 N背景（B6 N）具有低风险。PK 11195是Bzrp/TspO的一种有效的药理学配体，可保护B6 J胚胎免受酒精相关的眼缺陷。具体目标1将确定PK 11195反应性眼缺陷的遗传易感性是否与妊娠小鼠中胎儿酒精综合征的母体倾向有关。具体目标2将在全胚胎培养中使用遗传（B6 J，B6 N），药理学（PK 11195）和分子（反义）操作建立Bzrp/TspO和酒精诱导的眼缺陷之间的因果关系。具体目标3将确定受体介导的细胞粘附系统的microRNA（miRNA）的签名在酒精诱导的眼睛缺陷的发病机制改变。具体目标4将支持“出生缺陷系统管理器”（BDSM）作为一个持续的生物信息学知识管理系统，以实现相关发育和基因组数据的二次分析。实现这些具体目标将导致更好地了解与母亲饮酒相关的疾病风险，并可以推进对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.