COBRE: UNE MED CTR: P3: ETHANOL-RETINOID INTERATION IN INNER EAR MALFORMATIONS

COBRE：UNE MED CTR：P3：乙醇-维甲酸相互作用在内耳畸形中的作用

• 批准号: 7382085
• 负责人: JANEE GELINEAU-VAN WAES
• 金额: $ 19.88万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382085
• 关键词: COBRE; UNE; MED; CTR; P3

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The project, as initially proposed, involves using a molecular genetic approach to focus mechanistically on alterations in developmental events leading to malformations of the inner ear subsequent to prenatal alcohol exposure (Fetal Alcohol Syndrome; FAS). Epidemiological evidence suggests that approximately 30% of children affected with FAS experience sensorineural hearing loss, yet the underlying mechanisms are largely unknown. It was hypothesized that malformations of the inner ear/cochlea following in utero alcohol exposure resulted from a decrease in endogenous retinoic acid biosynthesis due to competition between alcohol and retinol for alcohol dehydrogenase enzyme pathways. This hypothesis was substantiated by in vitro experiments using an F9 cell line with a RARE-lacZ construct, in which a decrease in ?-galactosidase staining (positive for activation of the retinoic acid response element (RARE)) was demonstrated as increasing concentrations of ethanol were added to the media. Ethanol administration to pregnant dams of the inbred SWV murine strain resulted in offspring with multiple birth defects, including exencephaly, midfacial hypoplasia, cleft lip/palate, heart defects, and caudal regression, all of which were prevented when the mice were fed a diet rich in vitamin A. The impact of ethanol exposure on inner ear morphology was examined in both murine and chick embryo models. However, the teratogenic effects of maternal alcohol exposure were recognized to be very pleiotropic, and the project has re-focused on a single gene/pathway involved in a neurosensory system. The new proposal will investigate genetic/biochemical pathways regulated by microphthalmia-associated transcription factor (Mitf) in development of the retinal pigment epithelium (RPE) and in the stria vascularis of the inner ear. This will include the function of Mift in cell fate determination in the RPE and stria, its response to endothelial growth factors, and its role in modulating oxidative stress.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。该项目，如最初提出的，涉及使用分子遗传学的方法，集中在机制上的变化，在发展中的事件，导致畸形的内耳产前酒精暴露（胎儿酒精综合征; FAS）。流行病学证据表明，大约30%的FAS儿童患有感音神经性听力损失，但其潜在机制在很大程度上尚不清楚。据推测，宫内酒精暴露后内耳/耳蜗畸形是由于酒精和视黄醇之间竞争乙醇脱氢酶途径导致内源性视黄酸生物合成减少所致。这一假设得到了使用具有RARE-lacZ构建体的F9细胞系的体外实验的证实，在该实验中，半乳糖苷酶染色（对视黄酸反应元件（RARE）的活化呈阳性）随着乙醇浓度的增加而被证明。对近交系SWV小鼠品系的怀孕母鼠给予乙醇导致后代具有多种出生缺陷，包括露脑畸形、面中部发育不全、唇腭裂、心脏缺陷和尾部退化，当小鼠喂食富含维生素A的饮食时，所有这些都得到了预防。在小鼠和鸡胚胎模型中检查了乙醇暴露对内耳形态的影响。然而，母体酒精暴露的致畸作用被认为是非常多效性的，该项目已重新关注参与神经感觉系统的单个基因/通路。这项新的提案将研究在视网膜色素上皮（RPE）和内耳血管纹发育中由小眼症相关转录因子（Mitf）调节的遗传/生化途径。这将包括Mift在RPE和纹中的细胞命运决定中的功能，其对内皮生长因子的响应，以及其在调节氧化应激中的作用。