PREDISPOSITION TO DEVELOP PREECLAMPSIA

发生先兆子痫的倾向

• 批准号: 8166964
• 负责人: IRA MARK BERNSTEIN
• 金额: $ 1.11万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166964
• 关键词: Affect; Angiotensinogen; Asians; Blood Plasma Volume; Blood flow; Caucasians; Caucasoid Race; Chronic; Clinical; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Elderly; Funding; Future; Genetic Polymorphism; Genotype; Grant; Hydatidiform Mole; Institution; Link; Longitudinal Studies; Measurement; Phenotype; Physiological; Placentation; Platelet Activation; Population; Pre-Eclampsia; Predisposition; Pregnancy; Research; Research Personnel; Resources; Risk; Source; Third Pregnancy Trimester; Twin Multiple Birth; United States National Institutes of Health; Woman; constriction; mortality; neonatal morbidity; novel; pregnancy hypertension; pressure; prospective; theories

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Preeclampsia affects 3-5% of pregnancies and contributes significantly to maternal and neonatal morbidity and mortality. We have generated a novel hypothesis regarding the development of pre-eclampsia that postulates that two primary features contribute independently to its development. One feature is a pre-pregnancy phenotype that includes reduced plasma volume, elevated sympathetic tone, reduced uterine blood flow and enhanced platelet activation. This feature has been suggested by the association of a specific genetic polymorphism of angiotensinogen (TT 235) with an increased risk for pre-eclampsia. This polymorphism has been linked in our preliminary data to key pathophysiologic features of pre-eclampsia, previously thought to be exclusive to pregnancy, in women who are examined prior to pregnancy. The second feature is the physiologic volume expansion of pregnancy. We have theorized that the overt clinical manifestations of pre-eclampsia become apparent in late pregnancy as a result of either 1) a normal volume expansion in women unable to tolerate it due to a chronic adaptation to low intravascular volume (abnormal prepregnancy phenotype) or 2) an excessive volume expansion in women with a normal prepregnancy phenotype (i.e. twins, molar pregnancies). In this grant we propose to examine 3 primary specific aims, employing detailed whole body physiologic measurements in women, that will support this pathophysiologic view of the development of preeclampsia; 1) We will confirm that the angiotensinogen genotype that has been linked to preeclampsia in Caucasians and Asians is associated with reduced plasma volume in a nulligravid population and that this plasma volume constriction is associated with elevated sympathetic tone, reduced uterine blood flow and heightened platelet activation prior to pregnancy, 2) As we follow these women into pregnancy we will demonstrate; a) that low prepregnancy plasma volume is associated with elevated sympathetic tone and reduced uterine blood flow in early pregnancy (12 weeks) predisposing to abnormal placentation despite similar plasma volume expansion, and b) that prepregnancy plasma volume is indirectly related to both the change in mean arterial pressure (corrected for plasma volume expansion) and degree of platelet activation in the third trimester, 3) Finally, we will demonstrate that pregnancy results in an increase in both post-puerperal plasma volume and arterial compliance lowering the risk for both preeclampsia in future pregnancies and hypertension in later life. This will be a controlled prospective longitudinal study examining an integrated pathophysiologic mechanism underlying the development of preeclampsia. This study proposes to evaluate a novel hypothesis that synthesizes apparently contradictory data into a single coherent theory.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 先兆子痫影响3-5％的妊娠，并对母亲和新生儿的发病率和死亡率产生重大贡献。我们已经提出了一个关于前机会发展的新假设，该假设假设两个主要特征对其发展产生了独立贡献。一个特征是孕前表型，包括减少血浆体积，交感神经升高，子宫血流减少和血小板激活增强。这项特征是由血管紧张素原（TT 235）的特定遗传多态性与先兆子痫风险增加的相关性提出的。在我们的初步数据中，这种多态性已连接到前子女前的关键病理生理特征，以前认为在怀孕前检查的女性中，以前认为是妊娠的独有特征。第二个特征是妊娠的生理体积扩大。我们已经理论上，在怀孕后期，公开的临床表现显而易见，因为1）由于长期适应低血管内血管内体积（异常的孕前表征表型）或2）妇女过度扩张的妇女的慢性适应性（即正常的预期型（正常孕育）的妇女过度扩张，因此无法忍受的女性正常体积扩大。在这笔赠款中，我们建议在女性中采用详细的整个身体生理测量，以支持妇女的详细特定目的，这将支持先兆子痫发展的这种病理生理观点。 1）我们将确认，与高加索人和亚洲人的先兆子痫有关的血管紧张素原基因型与零子虫种群的血浆体积减少有关，并且这种血浆体积的收缩与交感神经升高有关，与升高的交感神经相关，子宫血流降低和降低的子宫流动和降低的血小板在怀孕之前，我们会在怀孕之前，2）妇女，我们将在怀孕中享受怀孕，我们将在怀孕之前; a）低孕前血浆体积与交感神经升高和妊娠早期子宫血流的升高有关（12周），尽管血浆体积膨胀相似，但易于异常胎盘，而b）血浆的血浆体积间接与平均含量的均值扩张和平均质量扩张相关的含量均与平均水平的变化相关）证明妊娠会导致培训后血浆体积和动脉依从性增加，从而降低了未来怀孕前脱位的风险和后来的高血压。这将是一项受控的前瞻性纵向研究，研究了先兆子痫发展的综合病理生理机制。这项研究建议评估一个新的假设，将显然矛盾的数据综合为单个连贯的理论。