Novel Ubiquitin Dependent Pathways Regulating Neural Tube Closure & Placentation

描述(申请人提供)：神经管和胎盘缺陷会导致妊娠期间的严重并发症。神经管缺陷，包括脊柱裂和无脑畸形，是影响人类的一些最常见的形态出生缺陷，导致胎儿死亡或长期残疾。胎盘发育缺陷可导致流产、先兆子痫或胎儿宫内发育受限。在小鼠身上的研究表明，神经管和胎盘的发育都需要大量基因的活性，我们才刚刚开始了解这些基因是如何组织成控制发育的途径的。此外，这些通路的活性如何被微调以更严格地控制蛋白质作用的强度和持续时间仍是未知的。泛素化是一种翻译后修饰，在调节蛋白质活性方面起着重要作用。泛素化的重要性通过泛素化途径的中断引起的许多人类疾病来说明，包括安杰曼斯综合症和帕金森氏病。尽管人们认识到泛素化的重要性，但它在胚胎发育过程中控制蛋白质活性的作用才刚刚开始被认识到。我们发现了一种新的泛素连接酶，它在神经管闭合和胎盘形成中起着关键作用。我们的目标是了解这种新型泛素连接酶对蛋白质功能的调节如何调节神经管和胎盘的发育。这里提出的实验将表征这个小鼠突变的胎盘表型，以提供对调控途径的有价值的洞察。此外，我们将使用生化、细胞生物学和遗传学方法来鉴定泛素连接酶的底物，泛素连接酶在我们的突变小鼠系中介导神经管和胎盘缺陷。这些实验将确定这种新型泛素连接酶调控神经管和胎盘发育的途径。 公共卫生相关性：这项提案的目标是确定一种新的泛素连接酶调控的通路，该酶对神经管和胎盘的发育至关重要。神经管和胎盘缺陷会导致妊娠期间严重的并发症，包括脊柱裂、流产、长期残疾、先兆子痫和胎儿生长受限。从这里提出的实验中获得的理解可能会导致将这些妊娠并发症降至最低的策略。

DESCRIPTION (provided by applicant): Neural tube and placental defects result in severe complications during pregnancy. Neural tube defects including spina bifida and anencephaly are some of the most common morphological birth defects affecting humans resulting in death of the fetus or long-term disability. Defects in development of the placenta can lead to miscarriage, preeclampsia or intrauterine growth restriction. Studies in mouse have demonstrated that both neural tube and placental development require the activity of a large number of genes and we are only beginning to understand how these genes organize into pathways to control development. Additionally, how the activity of these pathways is fine-tuned to more tightly control the strength and duration of protein action remains unknown. Ubiquitination is a posttranslational modification that plays an important role in regulating protein activity. The importance of ubiquitination is illustrated by the numerous human diseases caused by disruption of ubiquitination pathways including Angelmans Syndrome and Parkinson's disease. In spite of the recognized importance of ubiquitination, its role in controlling protein activity during embryonic development is only beginning to become appreciated. We identified a novel ubiquitin ligase that plays a critical role in neural tube closure and placentation. Our goal is to understand how regulation of protein function by this novel ubiquitin ligase regulates development of the neural tube and placenta. Experiments proposed here will characterize the placenta phenotypes in this mouse mutant to provide valuable insight into the pathways regulated. Additionally, we will use biochemical, cell biological and genetic approaches to identify the substrate of the ubiquitin ligase that mediates neural tube and placental defects in our mutant mouse line. These experiments will define the pathways regulated by this novel ubiquitin ligase to control neural tube and placental development. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to identify the pathways regulated by a novel ubiquitin ligase critical for the development of the neural tube and placenta. Neural tube and placental defects result in severe complications during pregnancy including spina bifida, miscarriage, long-term disability, preeclampsia and intrauterine growth restriction. The understanding gained from the experiments proposed here may lead to strategies to minimize these complications of pregnancy.