Cardiovascular disease, preeclampsia, and microchimerism

项目总结 心血管疾病(CVD)是全球女性死亡的主要原因，与性别有关的 疾病表型中的二形性。生殖事件可能在妇女先兆子痫(PE)中起作用 晚年患心血管疾病的风险大约增加2-8倍。尽管共同的风险因素肯定会对 一些流行病学数据表明，怀孕本身可能会带来一些风险。一次持久的怀孕- 特定的生理学是胎儿微嵌合体(FMC)，少量的胎儿细胞在发育过程中转移到母亲体内 怀孕，在分娩后几十年内都可以检测到。产科因素可能会影响这种转移，并且 已知的细胞FMC获得率在诊断时在PE妊娠妇女中较高。 重要的是，FMC细胞的持久性与可能由移植物引起的晚年自身免疫性疾病有关。 与导致炎症变化的宿主反应相比较。类似的机制可能在心血管疾病中起作用。 发展，证据是动脉粥样硬化和血管功能障碍增加的妇女注意到 有PE孕产史。在晚年成人疾病中详细评估FMC的一个限制是 检测FMC本身的方法学。目前的技术依赖于母体和子代的基因分型来检测 非共享的多态，然后使用定制的，基于细胞系的定量PCR分析。这个多- STEP过程繁重，在生育后年份或使用现有的方法往往不可行 由于缺乏家庭样本，导致了相关疾病的队列，如心血管疾病。当前的下一代测序 (NGS)技术有望克服这些限制。这项提案的首要目标是 通过检验女性心血管疾病与PE之间的假说来探讨心血管疾病与PE之间的新途径 有PE妊娠史的患者中，持续性FMC的发生率更高，水平更高 与怀孕不复杂的女性相比。同时，我们还将扩大其适用性 先进的NGS方法用于FMC检测和量化，以催化重要的研究 了解这一独特现象对心血管疾病和其他疾病的影响。通过这些 通过共同努力，我将在心血管疾病研究和分子技术方面获得专业知识，以便更好地了解 疾病的生殖起源，帮助我确立了作为一名翻译内科科学家的职业生涯。

PROJECT SUMMARY Cardiovascular disease (CVD) is the leading global cause of mortality in women, with significant sexual dimorphism in disease phenotypes. Reproductive events may play a role as women with preeclampsia (PE) carry an approximately 2-8 fold increased risk for CVD later in life. Although shared risk factors certainly play a role, some epidemiologic data suggests that pregnancy itself may confer some risk. One durable pregnancy- specific physiology is fetal microchimerism (FMc), a small number of fetal cells transferred to the mother during pregnancy, which are detectable for decades after delivery. Obstetric factors may influence this transfer, and cellular FMc acquisition is known to be higher in women with PE pregnancies at the time of diagnosis. Importantly, persistence of FMc cells is implicated in later-life autoimmune disease possibly due to a graft versus host response resulting in inflammatory change. A similar mechanism may be at play in CVD development, as evidenced by increased atherosclerosis and vascular dysfunction noted in women with a history of PE pregnancies. One limitation of detailed assessment of FMc in later-life adult disease is the methodology of detecting FMc itself. Current techniques rely on maternal and offspring genotyping to detect non-shared polymorphisms followed by use of customized, cell-line based quantitative PCR assays. This multi- step process is burdensome and often not feasible in post-reproductive years or using currently existing cohorts of relevant diseases, such as CVD, due to lack of family samples. Current next-generation sequencing (NGS) technologies hold promise in overcoming these limitations. The overarching goal in this proposal is to investigate a novel pathway between CVD and PE by testing the hypothesis that women with CVD and a history of PE pregnancy will more frequently harbor persistent FMc and at greater levels compared to women with uncomplicated pregnancies. Parallel to this, we will expand the applicability of an advanced NGS approach for FMc detection and quantification to catalyze important studies for understanding the implications of this unique phenomenon in CVD and other diseases. Through these combined efforts, I will gain expertise in CVD research and molecular techniques to better understand reproductive origins of disease, helping to establish my career as a translational physician scientist.