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

研究三手烟对血小板功能和血栓形成的影响

• 批准号: 10842614
• 负责人: Fadi T Khasawneh
• 金额: $ 10.86万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10842614
• 关键词: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; Acrolein; Address; Adverse effects; Agonist; Air; Animal Diseases; Animal Model; Anti-Inflammatory Agents; Awareness; Benzo(a)pyrene; Biochemical; Biochemical Markers; Biology; Blood Cells; Blood Platelet Disorders; Blood Platelets; California; Cardiovascular system; Child; Clot retraction; Coagulation Process; Cotinine; DNA Methylation; Data; Dependence; Development; Disease; Dose; Elements; Epigenetic Process; Epoprostenol; Exhibits; Exposure to; Foundations; Frequencies; Gender; Generations; Goals; Health; Hemostatic function; Hispanic Americans; Human; Impaired wound healing; In Vitro; Inflammatory; Integrins; Isoprene; Life; Literature; Mediating; MicroRNAs; Minority; Mus; Nature; Nicotine; Pathogenesis; Phenotype; Physiological; Plasma; Platelet Activation; Platelet Count measurement; Platelet aggregation; Play; Policies; Prevention; Process; Public Health; Risk; Role; Shapes; Smoke; Smoking; Societies; Stimulus; System; Therapeutic; Thrombin; Thrombosis; Thromboxane A2; Time; Tobacco; Tobacco Use Cessation; Tobacco use; Toxic effect; Toxin; Vulnerable Populations; cardiovascular disorder risk; cardiovascular health; clinically relevant; comparison control; cytokine; design; environmental tobacco smoke; evidence base; experimental study; exposed human population; in vivo; member; mortality; pharmacologic; platelet function; receptor; response; smoking cessation; thirdhand smoke; thrombogenesis; tobacco control; tobacco exposure; toxicant; virtual

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.

即使吸烟正在下降，死亡率并没有相称的降低 和与之相关的不利影响，尤其是在诸如儿童和少数民族之类的脆弱人群中（例如， 西班牙裔美国人）。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理中有充分的文献证明，新发现的“发现”的贡献 此类疾病过程的第三手烟（THS）仍然未知。这部分源自：（1）初始 缺乏对存在的知识； （2）缺乏对其“实际”负面健康后果的欣赏； （3）缺乏 模仿现实生活中的Ths-ths-ths-of侵蚀动物模型； （4）缺乏有关此类的研究 血小板生物学的后果。目前的申请建议实验，以解决基本的实验， 机械，表观遗传和与临床相关的转化方面的不良健康影响 在血栓性疾病和血小板生物学的背景下以及性别中的“实现”吸烟形式 具体方式。还建议以类似的方式研究研究的毒物 对血小板和相关疾病的影响。考虑到怀疑论，这些研究至关重要 关于存在和/或它的危险是/仍然被低估/未欣赏的目的地的事实 证据表明它比SHS更具毒性。我们提案的目的是： 目标1。研究暴露对血小板依赖性疾病状态的影响。同时引人注目 最近的证据表明，暴露于THS确实会产生负面影响，其对血小板的影响 - 依赖性疾病和性别对这些影响的贡献仍然未知。为了解决这个问题，我们 将确定在剂量，时间， 和依赖性别的时尚。随后的研究将检查THS是否参与发展 血栓性疾病以及研究凝血系统在介导其毒性中的作用。我们的 初步数据首次表明THS调节生理止血，表明它可能 增加心血管疾病的风险。 AIM 2。研究THS暴露调节血小板功能的机制。而我们的 初步研究表明，THS调节了止血，该机制将其模块调节 功能仍有待研究。这，本节提出的实验的总体目标是 确定暴露于各种血小板功能反应，细胞因子，血小板的重要性 表观遗传学，血栓形成“标记”和其他血细胞。还提出了研究研究是否 作用是受体介导的。值得注意的是，我们的初步数据表明THS确实增强了血小板 函数（例如聚合）。 AIM 3。定义对血小板依赖性疾病和功能的潜在影响的THS毒素。而有些 在影响血小板激活的特定FHS和SHS毒物/成分方面取得了进展 实际上，在THS的背景下什么都不知道。为此，最近的研究，包括加利福尼亚的研究 THS联盟（Martins-Green博士是创始成员），表明Nicotine，Cotinine，3-- Ethynylpyridine，Benzo（A）Pyrene，Nnal和Acrolein是THS的主要毒物之一。那， 这些毒物的影响，单独或组合对血小板功能和相关疾病的影响将被研究， 根据目标1和2中描述的方法；为了识别最潜在的毒物。为此，我们的 初步数据表明，可替宁 - THS的主要组成部分之一确实可以增强血小板 功能。 总的来说，这些实验将为我们的理解做出重大贡献 暴露的后果（一种未欣赏的健康威胁）对血小板激活和 心血管人类健康以及机制（例如表观遗传学）和有毒物质/通过/通过 它以特定性别的方式执行这些效果。