Placental injury and adaptation

描述(由申请人提供)：本提案以宫内生长受限(IUGR)为中心，它会导致早期新生儿发病率和死亡率，并与儿童时期的发育迟缓和神经行为功能障碍有关。此外，胚胎生长不足与成年后的代谢紊乱有关，包括高血压、冠状动脉疾病、高脂血症和胰岛素抵抗。完整的胎盘功能依赖于胎母交界处的绒毛滋养层，它完成胚胎发育的关键功能，包括气体交换、营养物质的供应和废物的清除、内分泌调节和免疫防御。不同的物理、化学和生物应激源对滋养层细胞损伤、适应和再生之间的动态平衡造成不利影响，导致胎盘功能障碍和胎儿生长不达标。这项建议是我们继续努力的一部分，目的是进一步了解滋养细胞损伤和适应的分子机制。我们推测，胎盘灌注不足，从而导致细胞缺氧，影响了一组独特的滋养细胞基因的表达，导致了严重的绒毛损害。随着人类基因组测序的完成，发现导致疾病或影响其进程的共同因素现在是指日可待的。使用高通量筛选，如寡核苷酸微阵列，对IUGR等复杂疾病特别有用，在IUGR中，一组复合基因产物决定发病机制，调节组织对侮辱的反应，甚至可能成为未来基因治疗的靶点。利用一种新的基因表达分析方法，我们确定结缔组织生长因子和卵泡抑素相关基因受低氧滋养层细胞的高度调控。我们假设这些糖蛋白在滋养层细胞中受低氧共同调节，并介导滋养层细胞对低氧损伤的反应。尽管之前在胎盘生物学的背景下还没有被探索，这些功能聚集的生长因子已经准备好调节滋养层细胞的损伤和修复。利用先进的工具，我们建立了这些生长因子在低氧滋养层细胞中的表达，剖析了它们的功能，并分析了它们在低氧反应中的调节。我们的研究结论可能有助于阐明绒毛损伤的机制，并可能为识别和处理IUGR及其后遗症提供新的工具。

DESCRIPTION (provided by applicant): This proposal centers on intrauterine growth restriction (IUGR), which causes early neonatal morbidity and mortality, and is implicated in developmental delay and neurobehavioral dysfunction during childhood. Moreover, inadequate embryonic growth is associated with metabolic disorders during adult life, including hypertension, coronary artery disease, hypeflipidemia and insulin resistance. Intact placental function depends on villous trophoblast at the feto-maternal interface, which fulfills critical functions for embryonic development, including gas exchange, supply of nutrients and removal of waste products, endocrine regulation and immunological defense. Diverse physical, chemical and biological stressors adversely influence the homeostatic balance between trophoblast injury, adaptation and regeneration, resulting in placental dysfunction and substandard fetal growth. This proposal is a part of our continuing effort to further our knowledge of molecular mechanisms that underlie trophoblast injury and adaptation. We surmise that placental under-perfusion, and consequently cellular hypoxia, impacts the expression of a unique set of trophoblast genes, resulting in a major villous insult. With the complete sequencing of the human genome, the discovery of shared factors that cause a disease or influence its course is now within reach. The employment of high-throughput screens such as oligonucleotide microarray is particularly useful for complex diseases such as IUGR, where a composite set of gene products determines pathogenesis, modulates tissue response to insult and may even serve as a target for future gene therapy. Using a novel approach to gene expression analysis we determined that connective tissue growth factor and follistatin-related gene are highly regulated by hypoxic trophoblasts. We hypothesize that these glycoproteins are co-regulated by hypoxia in trophoblasts, and mediate trophoblast response to hypoxic injury. Although previously unexplored in the context of placental biology, these functionally clustered growth factors are poised to regulate trophoblast injury and repair. Utilizing cutting-edge tools we establish the expression of these growth factors in hypoxic trophoblasts, dissect their function and analyze their regulation in response to hypoxia. Conclusions from our studies are likely to shed light on the mechanisms of villous injury, and may provide new tools to identify and manage IUGR and its sequelae.