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

基本信息

批准号：
10675546
负责人：
Fadi T Khasawneh
金额：
$ 37.88万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
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/10675546
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

项目摘要

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.

尽管吸烟率一直在下降，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民族等弱势群体（例如，（西班牙裔美国人）同时涉及众所周知的一手烟（FHS）和二手烟。（SHS）在血栓性疾病发病机制中的作用已有充分记录，新“发现”的贡献三手烟（THS）对此类疾病过程的影响尚不清楚，部分原因在于：（1）最初。缺乏对 THS 存在的认识；(2) 缺乏对其“真实”负面健康后果的认识；(3) 缺乏对其“真实”负面健康后果的认识；模拟现实生活场景的 THS 暴露动物模型；(4) 缺乏关于此类的研究；本申请提出了解决基本问题的实验，新疗法对健康不利影响的机制、表观遗传学和临床相关转化方面在血栓性疾病和血小板生物学的背景下，以及在性别方面，吸烟的“现实”形式，THS 还建议以类似的方式研究 THS 背后的有毒物质。鉴于人们的怀疑，这些研究具有重要意义。关于 THS 的存在和/或它的危险被/仍然被低估/未被认识到的事实，尽管有证据表明它比 SHS 毒性更大我们提案的目的是：目标 1. 研究 THS 暴露对血小板依赖性疾病状态的影响，同时令人信服。最近的证据表明，接触 THS 确实会对健康产生负面影响，它对血小板的影响依赖性疾病以及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 THS 暴露对正常止血和血小板计数的影响，剂量、时间、后续研究将检验 THS 是否参与了开发。血栓性疾病的研究，以及研究凝血系统在介导其毒性中的作用。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。目标 2. 研究 THS 暴露调节血小板功能的机制。初步研究表明，THS 调节止血，其机制是调节血小板因此，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、血小板的重要性还建议进行表观遗传学、血栓形成“标记物”和其他血细胞研究来调查 THS 是否存在。值得注意的是，我们的初步数据表明 THS 确实能增强血小板。功能（例如聚合）。目标 3. 明确 THS 毒素对血小板依赖性疾病和功能的影响。在影响血小板活化的特定 FHS 和 SHS 毒物/成分方面已取得进展，为此，最近的研究（包括加利福尼亚州的研究）对 THS 的情况几乎一无所知。 THS 联盟（Martins-Green 博士是该联盟的创始成员）已证明尼古丁、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。将研究这些毒物单独或组合对血小板功能和相关疾病的影响，根据目标 1 和 2 中描述的方法，以确定最有效的毒物。初步数据显示，THS 的主要成分之一可替宁确实能增强血小板功能。总的来说，这些实验将为我们理解 THS 暴露（一种未被意识到的健康威胁）对血小板活化的影响和心血管人类健康，以及机制（例如表观遗传学）和毒物它以针对特定性别的方式发挥这些影响。