Cardiovascular disease, preeclampsia, and microchimerism

项目摘要 心血管疾病（CVD）是全球女性死亡的主要原因， 疾病表型的二型性。生殖事件可能在先兆子痫（PE）妇女中发挥作用 在以后的生活中，CVD的风险增加约2-8倍。虽然共同的风险因素肯定会发挥作用， 然而，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- 一种特殊的生理学现象是胎儿微嵌合体（FMc），即少量胎儿细胞在胚胎发育过程中转移到母体。 怀孕，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， 已知在诊断时PE妊娠的妇女中细胞FMc获得更高。 重要的是，FMc细胞的持续存在与可能由移植物引起的晚年自身免疫性疾病有关 对抗宿主反应导致炎症变化。类似的机制可能在CVD中起作用 发展，如动脉粥样硬化和血管功能障碍的增加所证明， PE妊娠史。在成年后期疾病中详细评估FMc的一个局限性是 检测FMc本身的方法。目前的技术依赖于母体和后代的基因分型来检测 非共享多态性，然后使用定制的基于细胞系的定量PCR测定。这多- 分步过程是繁重，且在生育后的年份或使用现有的 由于缺乏家庭样本，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。本提案的总体目标是 通过检验以下假设来研究CVD和PE之间的新途径： 有PE妊娠史者更常出现持续性FMc，且FMc水平更高 与单纯妊娠的女性相比。与此同时，我们将扩大适用性 先进的NGS方法用于Fmc检测和定量，以催化重要的研究， 了解这一独特现象在CVD和其他疾病中的意义。通过这些 通过共同努力，我将获得CVD研究和分子技术方面的专业知识，以更好地了解 疾病的生殖起源，帮助我建立了作为一名转化医学科学家的职业生涯。

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.