IMPACT OF ENDOTHELIN IN INTRAUTERINE GROWTH RESTRICTION

内皮素对宫内生长受限的影响

• 批准号: 6758657
• 负责人: LARRY G THAETE
• 金额: $ 8万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-18 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6758657
• 关键词: blood cell count; endothelin; enzyme activity; enzyme inhibitors; gene expression; genetic regulation; hormone inhibitor; hormone regulation /control mechanism; hypoxia; immunocytochemistry; in situ hybridization; laboratory rat; nitric oxide; nitric oxide synthase; northern blottings; pathologic process; placenta disorders; polymerase chain reaction; preeclampsia; pregnancy circulation; prenatal growth disorder; protein localization; proteinuria; thrombocytopenia

DESCRIPTION (Adapted from applicant's description): Intrauterine growth restriction (IUGR) occurs in 4 to 7% of all infants delivered in developed countries, and is a major contributor to perinatal morbidity and mortality. Inadequate uteroplacental perfusion is fundamental to most cases of IUGR in humans. Endothelin-1 (ET-1) and nitric oxide (NO) are vascular mediators which are important for the regulation of uterine and placental vascular tone. The investigators hypothesize that increased endogenous ET-1, a locally active vasoconstrictor, is critically important in the pathophysiology of IUGR. They will evaluate the molecular mechanisms regulating the activities of both ET-1 and NO in uteroplacental perfusion and IUGR. They also will evaluate the role of endogenous ET-1 in the pathophysiology of IUGR, using ET-1 receptor antagonists. The investigators will use two different animal models of IUGR which were selected because of the opportunity they provide to study the roles of these two mediators. 1) Chronic maternal hypoxia is a model of IUGR which is associated with increased endogenous ET-1 as well as decreased nitric oxide synthase (NOS) activity. This model will be used to evaluate the efficacy of ET-1 antagonists to improve uteroplacental perfusion and prevent IUGR. 2) Chronic NOS inhibition is another established model of IUGR which also is associated with increased circulating endogenous ET-1. Additionally, NOS inhibition in the rat mimics human preeclampsia, a condition commonly associated with IUGR. The investigators will use this model to evaluate whether ET-1 antagonism prevents the preeclampsia-like state, as well as IUGR, caused by chronic NOS inhibition. In each of these models, they will evaluate the molecular mechanisms which regulate ET-1 activity. Additionally, in the hypoxia model the investigators will evaluate the molecular mechanisms regulating NO activity. The goal is to better understand the regulation of uteroplacental perfusion, to delineate the molecular mechanisms regulating the synthesis and activity of ET-1 and NO, and, using ET-1 antagonists, to evaluate the specific role of ET-1 in the pathophysiology of IUGR.

描述（根据申请人的描述改编）：宫内生长 限制（IUGR）发生在4％至7％的发达婴儿中 国家，是围产期发病率和死亡率的主要贡献者。 子宫术灌注不足是大多数IUGR的基础 人类。内皮素-1（ET-1）和一氧化氮（NO）是血管介质的 对于子宫和胎盘血管张力的调节很重要。这 研究人员假设增加了内源性ET-1，一种局部活跃 血管收缩剂在IUGR的病理生理中至关重要。他们 将评估调节这两种ET-1活性的分子机制 在子宫腔灌注和IUGR中没有。他们还将评估角色 使用ET-1受体的IUGR病理生理学中的内源性ET-1 对手。调查人员将使用两种不同的IUGR动物模型 之所以选择是因为他们提供了研究角色的机会 在这两个调解人中。 1）慢性母体缺氧是IUGR的模型 与内源性ET-1的增加以及一氧化氮减少有关 合酶（NOS）活性。 该模型将用于评估 ET-1拮抗剂可以改善子宫腔灌注并预防IUGR。 2）慢性NOS抑制是IUGR的另一个既定模型，也是 与循环内源性ET-1的增加有关。另外，nos 大鼠模仿人类先兆子痫的抑制作用，这种情况通常是 与IUGR相关。调查人员将使用此模型评估 ET-1的拮抗作用是否阻止了前斜坡状的状态和IUGR， 由慢性NOS抑制作用。在每个模型中，他们都会评估 调节ET-1活性的分子机制。另外，在 缺氧模型研究者将评估分子机制 调节无活动。 目标是更好地了解 子宫灌注，以描述调节的分子机制 ET-1和NO的合成和活性，以及​​使用ET-1拮抗剂到 评估ET-1在IUGR病理生理学中的特定作用。