In Utero Third-Hand Smoke Impact on Platelet Function and Thrombogenesis

而宫内暴露于一手烟(FHS)和二手烟(SHS)在 血栓性疾病的发病机制是有据可查的，贡献于新发现的第三手 这种疾病过程中的形式(THS)仍不清楚。这在一定程度上源于：(1)最初缺乏知识 对THS的存在缺乏认识；(2)缺乏对其“真正的”负面健康后果的认识；(3)缺乏THS-Exosure 模拟真实世界场景的动物模型；以及(4)缺乏关于这种对血小板的影响的研究 生物学。本申请提出了解决基本的、机械的、表观遗传的和 临床相关的翻译方面的不良健康影响的新的“实现”形式的吸烟， 在子宫内和血栓性疾病和血小板生物学的背景下，以及性别。研究也在进行 建议以类似的方式调查导致THS对血小板和相关疾病影响的毒物 疾病。这些研究具有重要意义，因为THS的危险是 被低估/不被赏识，尽管有证据表明它比SHS毒性更大，特别是在脆弱的人群中 儿童和少数族裔(例如西班牙裔美国人)等群体。我们建议的目的是： 目的1.探讨宫内暴露THS对血小板依赖性疾病的影响。在子宫里的时候 暴露于众所周知的FHS和SHS被发现有助于心肌梗死的发生， 子宫内暴露于THS是否也与血栓性疾病的风险增加有关，目前尚不确定 下定决心。为了解决这个问题，我们将确定子宫内THS暴露对正常 止血，血小板计数，以及凝血因子和其他血栓形成介质，在剂量和时间- 依附时尚。随后的研究将检查在子宫内THS是否参与了 血栓性疾病。 目的2.探讨宫内THS暴露调节血小板功能的机制。我们的 最近发表的研究结果首次表明，成人接触THS可以调节生理止血， 并通过增强血小板活化增加血栓形成的风险。然而，无论是在子宫内，THS是 与类似的作用有关，如果是这样的话，它调节血小板功能的机制仍有待研究 调查过了。因此，本节中提出的实验的总体目标是确定重要性， 宫内暴露对多种血小板功能反应影响的毒物及机制， 血小板表观遗传学及其对其他血细胞(如白细胞)和血栓形成“标志物”的影响 接触的主要途径。 总的来说，这些实验将对我们理解 宫内THS暴露对血小板活化和心血管人类健康的影响 表观遗传学，以及THS发挥作用的机制和毒物。

While the involvement of in utero exposure to first-hand smoke (FHS) and second-hand smoke (SHS) in the pathogenesis of thrombotic diseases is well documented, the contribution of the newly “discovered” third-hand form (THS) in such disease processes remains unknown. This derives, in part, from: (1) initial lack of knowedlge of THS existence; (2) lack of appreciation for its “real” negative health consequences; (3) lack of a THS-exosure animal model that mimics real-world scenarios; and (4) lack of studies regarding such consequences on platelet biology. The present application proposes experiments that address fundamental, mechanistic, epigenetic and clinically-relevant translational aspects of the adverse-health effects of the newly “realized” form of smoking, THS, in utero and in the context of thrombotic disease and platelet biology, and gender. Studies are also proposed to investigate, in a similar fashion, the toxicants that underlie THS effects on platelets and associated diseases. These studies are of paramount significance given that the dangers of THS are underestimated/unappreciated, despite evidence that it is more toxic than SHS, especially in vulnerable populations such as children and minorities (e.g., Hispanic Americans). The Aims of our proposal are: Aim 1. Investigate the impact of in utero THS-exposure on platelet-dependent diseases. While in utero exposure to the well-known FHS and SHS was found to contribute to the genesis of myocardial infarctions, whether in utero exposure to THS is also associated with an increased risk of thrombotic disorders, is yet to be determined. To address this issue, we will determine the ramifications of in utero THS exposure on normal hemostasis, platelet counts, as well as on clotting factors and other thrombosis mediators, in a dose-, and time- dependent fashion. Subsequent studies will examine whether in utero THS participates in the development of thrombotic disorders. Aim 2. Investigate the mechanism by which in utero THS-exposure modulates platelet function. Our recently published findings show, for the first time, that adult THS exposure modulates physiological hemostasis, and increases the risk of thrombogenesis, via enhancing platelet activation. However, whether in utero THS is associated with similar effects, and if so, the mechanism by which it modulates platelet function remain to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the significance, toxicants and mechanism of the impact of in utero THS-exposure on various platelet functional responses, platelet epigenetics, its effect on other blood cells (e.g., leukocytes) and thrombosis “markers”, as well as its major route of exposure. Collectively, these experiments will make significant contributions to our understanding of the consequences of in utero THS exposure on platelet activation and cardiovascular human health, its epigenetics, and the mechanism and toxicants by which THS exerts its effects.