Investigate The Impact of Third-Hand Smoke on Platelet Function and Thrombogenesis

尽管吸烟一直在减少，但死亡率并没有相应下降。 以及与之相关的不利影响，特别是在弱势群体中，如儿童和少数群体(例如， 拉美裔美国人)。而众所周知的一手烟(FHS)和二手烟的介入 自发性硬化症(SHS)在血栓性疾病发病机制中的作用是有据可查的，其贡献是新“发现”的 三手烟雾(THS)对此类疾病过程的影响尚不清楚。这部分源于：(1)初始 对THS的存在缺乏了解；(2)对其“真正的”负面健康后果缺乏认识；(3)缺乏 模拟真实生活场景的THS-exosure动物模型；以及(4)缺乏关于这种情况的研究 对血小板生物学的影响。本申请提出了解决基本问题的实验， 新药不良健康影响的机械性、表观遗传学和临床相关的翻译方面 在血栓性疾病和血小板生物学的背景下，以及在性别上，实现了吸烟的形式，THS 具体的方式。还建议进行研究，以类似的方式调查THS背后的毒物 对血小板及相关疾病的影响。考虑到人们的怀疑，这些研究具有重要意义 关于THS的存在和/或其危险被/仍然被低估/未被认识的事实，尽管 有证据表明它比SHS毒性更大。我们建议的目的是： 目的1.研究THS暴露对血小板依赖性疾病状态的影响。虽然很有说服力 最近的证据表明，暴露在THS中确实会对健康产生负面影响，它对血小板的影响- 依存性疾病以及性别对这些影响的贡献仍不清楚。为了解决这个问题，我们 将确定暴露于THS对正常止血和血小板计数的影响，在剂量-，时间-， 和性别相关的时尚。随后的研究将检查THS是否参与了这一发展 血栓性疾病以及研究凝血系统在调节其毒性中的作用。我们的 初步数据首次显示，THS调节生理止血，这表明它可能 增加患心血管疾病的风险。 目的2.探讨THS暴露调节血小板功能的机制。而我们的 初步研究表明，THS调节止血，这是它调节血小板的机制 其功能有待进一步研究。因此，本节中提出的实验的总体目标是 确定THS暴露对血小板各种功能反应、细胞因子、血小板的影响 表观遗传学、血栓形成的“标志物”等血细胞。还建议进行研究，以调查THS 效应是由受体介导的。值得注意的是，我们的初步数据显示，THS确实能增强血小板 函数(例如，聚合)。 目的3.确定对血小板依赖性疾病和功能有显著影响的THS毒素。虽然有些人 在影响血小板活化的特定FHS和SHS毒物/成分方面取得了进展， 在THS的背景下，几乎什么都不知道。为此，最近的研究，包括加州大学的研究 该联盟(马丁斯-格林博士是其创始成员之一)表明，尼古丁、可替宁、3- 乙炔基吡啶、苯并(A)芘、NNAL以及丙烯醛是主要的THS毒物。因此， 这些毒物单独或联合使用对血小板功能和相关疾病的影响将被调查， 根据目标1和目标2中描述的方法；以确定最强的毒物。为此，我们的 初步数据显示，可替宁--THS的主要成分之一--确实能增强血小板 功能。 总的来说，这些实验将对我们理解 暴露于THS(一种未被意识到的健康威胁)对血小板活化和 心血管人类健康，以及机制(例如，表观遗传学)和毒物 它以一种针对性别的方式施加这些影响。

Even though smoking has been on the decline, there has not been a commensurate decrease in the mortality and adverse effects associated with it, especially in vulnerable populations such as children and minorities (e.g., Hispanic Americans). While the involvement of the well-known 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 smoke (THS) form to 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-life 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 the context of thrombotic disease and platelet biology, and in a gender- specific manner. 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 the skepticism regarding THS existence and/or the fact that its dangers are/remain underestimated/unappreciated, despite evidence that it is more toxic than SHS. The Aims of our proposal are: Aim 1. Investigate the impact of THS-exposure on platelet-dependent disease states. While compelling recent evidence revealed that exposure to THS does exert negative health effects, its impact on platelet- dependent diseases and the contribution of gender to these effects are still unknown. To address this issue, we will determine the ramifications of THS exposure on normal hemostasis and platelet counts, in a dose-, time-, and gender-dependent fashion. Subsequent studies will examine whether THS participates in the development of thrombotic disease, as well as investigate the role of the coagulation system in mediating its toxicity. Our preliminary data shows, for the first time, that THS modulates physiological hemostasis, suggesting that it may increase the risk of cardiovascular disease. Aim 2. Investigate the mechanism by which THS-exposure modulates platelet function. While our preliminary studies revealed that THS modulates hemostasis, the mechanism, by which it modules platelet function remains to be investigated. Thus, the overall goal of the experiments proposed in this section is to determine the significance of THS-exposure on the various platelet functional responses, cytokines, platelet epigenetics, thrombosis “markers” and other blood cells. Studies are also proposed to investigate whether THS effects are receptor mediated. It is noteworthy that our preliminary data shows that THS does enhance platelet function (e.g., aggregation). Aim 3. Define THS toxins with potent impact on platelet-dependent disease and function. While some progress has been made regarding specific FHS and SHS toxicants/ingredients that impact platelet activation, virtually nothing is known in the context of THS. To this end, recent studies, including those by the California THS Consortium (for which Dr. Martins-Green was a founding member), have shown that nicotine, cotinine, 3- ethynylpyridine, benzo(a)pyrene, NNAL, as well as acrolein, are amongst the major THS toxicants. Thus, the impact of these toxicants, alone or in combination, on platelet function and related disease will be investigated, as per the approaches described in Aims 1 and 2; in order to identify the most potent toxicants. To this end, our preliminary data revealed that cotinine- one of the major components of THS- does indeed enhance platelet function. Collectively, these experiments will make significant contributions to our understanding of the consequences of THS exposure (an unappreciated health threat) on platelet activation and cardiovascular human health, as well as the mechanism (e.g., epigenetics) and toxicants by/through which it exerts these effects, in a gender-specific manner.