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

尽管吸烟人数一直在减少，但死亡率并没有相应下降 以及与之相关的不利影响，特别是对儿童和少数群体等弱势群体的影响（例如， 西班牙裔美国人）。虽然众所周知的第一手烟（FHS）和二手烟的参与 (SHS)在血栓性疾病的发病机制中有很好的记载，新“发现”的 三手烟（THS）形式对这种疾病过程的影响仍然未知。这部分源于：（1）初始 缺乏对THS存在的了解;（2）缺乏对其“真实的”负面健康后果的认识;（3）缺乏 模拟现实生活场景的THS-exosure动物模型;以及（4）缺乏关于此类研究的研究 对血小板生物学的影响。本申请提出了解决基本的， 机制，表观遗传和临床相关的翻译方面的不良健康影响的新 在血栓性疾病和血小板生物学的背景下，以及在性别方面， 具体方式。研究也提出了调查，以类似的方式，有毒物质的基础THS 对血小板和相关疾病的影响。这些研究是至关重要的意义， 关于THS的存在和/或其危险被低估/不被重视的事实，尽管 有证据表明它比SHS更有毒。我们建议的目的是： 目标1.研究THS暴露对血小板依赖性疾病状态的影响。虽然引人注目 最近的证据显示，暴露于THS确实会对健康产生负面影响，其对血小板的影响， 依赖性疾病以及性别对这些影响的影响仍然未知。为了解决这个问题，我们 将确定THS暴露对正常止血和血小板计数的影响，剂量，时间， and gender性别dependent依赖fashion时尚.其后的研究会探讨房屋署有否参与发展 血栓性疾病，以及研究凝血系统在介导其毒性的作用。我们 初步数据首次显示，THS调节生理性止血，这表明它可能 增加患心血管疾病的风险。 目标2.研究THS暴露调节血小板功能的机制。虽然我们的 初步研究表明，THS调节止血，其调节血小板的机制 功能还有待研究。因此，本节提出的实验的总体目标是： 确定THS暴露对各种血小板功能反应、细胞因子、血小板聚集和血小板聚集的意义。 表观遗传学、血栓形成“标记物”和其他血细胞。研究还建议调查THS是否 效应是受体介导的。值得注意的是，我们的初步数据显示，THS确实能增强血小板聚集， 功能（例如，聚合）。 目标3：定义THS毒素对血小板依赖性疾病和功能的有效影响。虽然一些 关于影响血小板活化的特定FHS和SHS毒物/成分已经取得了进展， 实际上在THS的上下文中什么都不知道。为此，最近的研究，包括那些由加州 THS联盟（Martins-Green博士是该联盟的创始成员）已经表明，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 将研究这些毒物单独或组合对血小板功能和相关疾病影响， 按照目标1和2所述的方法;以确定最强的毒物。为此，我们 初步数据显示，可替宁--THS的主要成分之一--确实能增强血小板聚集， 功能 总的来说，这些实验将对我们理解 THS暴露（一种未被认识到的健康威胁）对血小板活化的影响， 心血管人类健康，以及机制（例如，表观遗传学）和毒物 它以性别特异的方式发挥这些作用。

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.