Placental injury and adaptation

描述（由申请人提供）：该提案以宫内生长受限（IUGR）为中心，IUGR会导致早期新生儿发病率和死亡率，并与儿童期发育迟缓和神经行为功能障碍有关。此外，胚胎发育不足与成年期的代谢紊乱有关，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儿-母体界面的绒毛滋养层，其实现胚胎发育的关键功能，包括气体交换，营养供应和废物清除，内分泌调节和免疫防御。各种物理、化学和生物应激源对滋养细胞损伤、适应和再生之间的稳态平衡产生不利影响，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，以进一步了解滋养层损伤和适应的分子机制。我们推测，胎盘灌注不足，因此细胞缺氧，影响一组独特的滋养层基因的表达，导致一个主要的绒毛损伤。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已经触手可及。采用高通量筛选，如寡核苷酸微阵列是特别有用的复杂疾病，如IUGR，其中一组复合的基因产物决定发病机制，调节组织的反应，侮辱，甚至可以作为未来的基因治疗的目标。利用一种新的基因表达分析方法，我们确定了结缔组织生长因子和卵泡抑素相关基因的高度调节缺氧滋养细胞。我们推测，这些糖蛋白是共同调节的滋养细胞缺氧，并介导滋养细胞缺氧损伤的反应。虽然以前未探索的背景下，胎盘生物学，这些功能聚集的生长因子准备调节滋养层损伤和修复。利用尖端的工具，我们建立了这些生长因子在缺氧滋养细胞中的表达，剖析了它们的功能，并分析了它们对缺氧的调节。我们的研究结论可能揭示绒毛损伤的机制，并可能提供新的工具，以识别和管理IUGR及其后遗症。

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.