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

虽然子宫内暴露于第一手烟雾（FHS）和二手烟雾（SHS）的参与， 血栓性疾病的发病机制是有据可查的，新“发现”的第三手的贡献 在这种疾病过程中的THS形式仍然未知。这部分源于：（1）最初缺乏知识 （2）缺乏对其“真实的”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、表观遗传的和遗传学的实验。 新“实现的”吸烟形式的不良健康影响的临床相关转化方面， THS，在子宫内和血栓性疾病和血小板生物学的背景下，和性别。研究也 建议以类似的方式调查THS对血小板和相关细胞影响的毒性物质。 疾病这些研究具有极其重要的意义，因为THS的危险是 被低估/未被重视，尽管有证据表明它比SHS更具毒性，特别是在脆弱的 例如儿童和少数民族（例如，西班牙裔美国人）。我们建议的目的是： 目标1。研究宫内THS暴露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塞的发生， 子宫内暴露于THS是否也与血栓性疾病的风险增加有关，还有待进一步研究。 测定为了解决这个问题，我们将确定子宫内THS暴露对正常人的影响。 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- 依赖的方式。随后的研究将检查子宫内THS是否参与了 血栓性疾病 目标2.研究子宫内THS暴露调节血小板功能的机制。我们 最近发表的研究结果首次表明，成人THS暴露调节生理止血， 并通过增强血小板活化而增加血栓形成的风险。然而，无论在子宫内THS是 与类似的作用相关，如果是这样，它调节血小板功能的机制仍然是 研究了因此，本节中提出的实验的总体目标是确定显著性， 毒物和宫内THS暴露对各种血小板功能反应的影响机制， 血小板表观遗传学，其对其它血细胞的影响（例如，白细胞）和血栓形成“标记物”，以及其 暴露的主要途径。 总的来说，这些实验将对我们理解 子宫内THS暴露对血小板活化和人类心血管健康的影响， 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.