Regulation of maspin in placental development

maspin 在胎盘发育中的调节

• 批准号: 6637777
• 负责人: ANUJA DOKRAS
• 金额: $ 9.8万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637777
• 关键词: cell migration; cell morphology; cell motility; clinical research; endometrium; enzyme activity; enzyme mechanism; gene expression; genetic regulation; growth /development; human genetic material tag; human tissue; hypoxia; patient oriented research; placenta; preeclampsia; prenatal growth disorder; protease inhibitor; serine proteinases; superoxide dismutase; tissue /cell culture; transfection; trophoblast; tumor suppressor genes; western blottings

DESCRIPTION (provided by applicant): Placental invasion is a highly regulated process and impairment results in pathologic obstetric conditions such as preeclampsia and intra-uterine growth restriction (IUGR). Further identification of factors that play a role in modifying this invasive ability of cytotrophoblasts will contribute to a better understanding of this unique developmental process. We have demonstrated a specific timeline for the expression of maspin, novel tumor suppressor gene in placental invasion and development. Our findings show that maspin is maximally expressed in the third trimester with low levels of expression in the first trimester of pregnancy. The specific aims of this proposal are 1) To measure the biological consequence(s) of maspin up regulation in human cytotrophoblasts with respect to invasion, motility and morphogenesis in vitro 2) Examine the role of hypoxia in regulating maspin expression in cytotrophoblasts 3) Compare the abundance of maspin/manganese superoxide dismutase mRNA and protein in placentas from women with term and preterm deliveries, with and without preeclampsia. The research design will include using adenoviral approach to transfect maspin into primary trophoblast cultures during the first and second testers and examine the effects of this transfection on cell invasion, migration, motility and morphogenesis. Next, the effects of hypoxia on maspin expression and the role of hypoxia-inducible factor in mediating these effects will be examined. Finally, will confirm our hypothesis using an in vivo model of hypoxia and impaired cytotrophoblast invasion namely preeclampsia. Maspin expression will be compared in placentae from women with preeclampsia to those from normal controls using real-time PCR. The long-term objectives of this project are two-fold, first, to understand the significance and mechanism(s) of action of tumor suppressor genes such as maspin in human placental development second, to identify pathological processes during gestation arising from alterations of maspin expression. Information revealed in this study could have profound implications on therapeutic strategies for clinical conditions associated with decreased cytotrophoblast invasion such as preeclampsia and IUGR. In addition, any important new information that may be obtained about the putative role of maspin during embryonic development may help elucidate the biological significance of its loss during tumor progression.

描述（由申请人提供）：胎盘入侵是一个高度调节的过程，损害导致病理性产科状况，例如先兆子痫和 - 局内生长限制（IUGR）。进一步识别在修改细胞增生细胞的这种侵入性能力方面发挥作用的因素将有助于更好地理解这一独特的发展过程。我们已经证明了Maspin表达的特定时间表，Maspin，新型肿瘤抑制基因在胎盘侵袭和发育中。我们的发现表明，在妊娠前三个月表达低水平的三个月中，马斯皮素是最大表达的。该提案的具体目的是1）测量Maspin的生物学后果（S）在人类细胞增多质细胞中的调节在体外的侵袭，运动性和形态发生方面的生物学作用2）检查缺氧在调节MASPOPHRASTS中的MASPIN表达中的缺氧在调节MASPIROPHASTS中的培养基中的培养基/蛋白酶超级氧化物中的培养基中的培养基超级氧化物中的术语序列序列序言，该作用与Mangutsexexiidide的培养基中的培养量相似。早产，有和没有先兆子痫。研究设计将包括使用腺病毒方法在第一和第二个测试仪期间将Maspin转染到原代滋养细胞培养物中，并检查这种转染对细胞侵袭，迁移，运动和形态发生的影响。接下来，将研究缺氧对Maspin表达的影响以及缺氧诱导因子在介导这些作用中的作用。最后，将使用缺氧的体内模型证实我们的假设，并损害了细胞增生细胞侵袭，即先兆子痫。使用实时PCR，将在胎盘中比较Maspin表达与正常对照的胎盘表达。该项目的长期目标首先是两倍，以了解肿瘤抑制基因（例如MASPIN）在人胎盘发育中的重要性和机制，以鉴定由Maspin表达改变引起的妊娠过程中的病理过程。这项研究中揭示的信息可能对与胞质质细胞侵袭（如先兆子痫和IUGR）相关的临床状况的治疗策略具有深远的影响。此外，关于Maspin在胚胎发育过程中推定的作用的任何重要新信息都可能有助于阐明其在肿瘤进展过程中损失的生物学意义。