IMPACT OF ENDOTHELIN IN INTRAUTERINE GROWTH RESTRICTION

内皮素对宫内生长受限的影响

• 批准号: 6233077
• 负责人: LARRY G THAETE
• 金额: $ 7.32万
• 依托单位: EVANSTON HOSPITAL
• 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/6233077
• 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（改编自申请人的描述）：宫内生长 在发达国家分娩的所有婴儿中，有 4% 至 7% 发生宫内生长受限 (IUGR) 国家，并且是围产期发病率和死亡率的一个主要因素。 子宫胎盘灌注不足是大多数 IUGR 病例的根本原因 人类。内皮素-1 (ET-1) 和一氧化氮 (NO) 是血管介质， 对于子宫和胎盘血管张力的调节很重要。这 研究人员推测，内源性 ET-1（一种局部活性物质）增加 血管收缩剂，在 IUGR 的病理生理学中至关重要。他们 将评估调节 ET-1 活性的分子机制 子宫胎盘灌注和 IUGR 中的 NO。他们还将评估该角色 使用 ET-1 受体研究内源性 ET-1 在 IUGR 病理生理学中的作用 对手。研究人员将使用两种不同的 IUGR 动物模型 之所以选择这些人是因为他们提供了研究角色的机会 这两个调解人。 1）慢性母体缺氧是IUGR的模型 与内源性 ET-1 增加以及一氧化氮减少相关 合酶（NOS）活性。 该模型将用于评估 ET-1 拮抗剂可改善子宫胎盘灌注并预防 IUGR。 2）慢性NOS抑制是IUGR的另一种既定模型，也是 与循环内源性 ET-1 增加有关。此外，NOS 大鼠的抑制作用模仿了人类先兆子痫，这是一种常见的病症 与IUGR有关。研究人员将使用该模型来评估 ET-1拮抗剂是否可以预防子痫前期样状态以及IUGR， 由慢性NOS抑制引起。在每个模型中，他们都会评估 调节 ET-1 活性的分子机制。此外，在 缺氧模型研究人员将评估分子机制 调节NO活性。 目的是让大家更好地了解监管 子宫胎盘灌注，描绘调节的分子机制 ET-1 和 NO 的合成和活性，并且使用 ET-1 拮抗剂， 评估 ET-1 在 IUGR 病理生理学中的具体作用。