The Role of Klotho and TRPA1 in Vitamin D Deficiency and Air Pollution-induced Cardiopulmonary Dysfunction

项目摘要 人类研究表明，空气污染与心血管疾病的发病率有关，但 营养在改变这种易感性中的作用尚不清楚。维生素D缺乏症（VDD） 成为一个公共卫生问题，以及它与其他 压力源需要被理解。VDD与低水平的抗衰老蛋白Klotho有关 在窦房功能中起关键作用。因此，我假设VDD会影响心血管系统， 空气污染暴露引发的功能障碍，特别是心律失常，由于低klotho 表情我们以前的数据表明，空气污染引起的心血管影响是 由瞬时受体电位（TRP）刺激通道介导，特别是TRPA 1， 由Klotho监管。因此，我推测VDD对这些影响的恶化是由于klotho- 引起TRPA 1功能的改变。首先，我将确定早期生活VDD对 小鼠对光化学烟雾的心血管反应，并评估VDD是否导致 表观遗传变化沉默klotho表达。三周龄的小鼠将被放置在 VDD或正常饮食16周。小鼠要么通过手术植入生物电位 无线电遥测仪连续测量心电图（ECG）和心率，或将 在整个饮食过程中进行超声心动图（Echo）和全身体积描记术（WBP）， 分别在烟雾暴露前和烟雾暴露后追踪心脏和呼吸功能。小鼠将 然后暴露在复杂的烟雾混合物或过滤空气中。将分析ECG， 间期、心律失常和心率变异性（HRV）。第二，DNA甲基化状态 还将评估klotho以及klotho和TRPA 1的基因表达。最后，我们将 研究klotho对TRPA 1的调节是否在VDD诱导的 空气污染对心血管的影响TRPA 1的参与将由以下因素决定： 将小鼠暴露于丙烯醛中，丙烯醛是TRPA 1激动剂。小鼠将接受重组治疗 在先前描述的VDD饮食方案结束时，将klotho或盐水持续3周，以 确定增强效应是否被阻断。ECG、HRV、超声心动图和WBP将按照 功能评估。该项目将是第一个描述VDD在以下方面的作用的项目： 对空气污染的心血管反应恶化这项工作还将明确机制 通过这种方式，早期生活VDD使心血管系统对空气污染引起的 功能障碍

Project Summary Human studies have shown that air pollution is associated with cardiovascular morbidity, yet the role of nutrition in modifying this susceptibility is unclear. Vitamin D deficiency (VDD) has become a public health concern and the adverse consequences of its interaction with other stressors needs to be understood. VDD is linked to low levels of klotho, an anti-aging protein with a critical role in sinoatrial function. Thus, I hypothesize that VDD worsens cardiovascular dysfunction triggered by air pollution exposure, especially arrhythmia, due to lower klotho expression. Our previous data show that air pollution-induced cardiovascular effects are mediated by transient receptor potential (TRP) irritant channels, specifically TRPA1, which are regulated by klotho. Thus, I surmise that worsening of these effects by VDD is due to klotho- induced changes in TRPA1 function. First, I will determine the effect of early-life VDD on cardiovascular responses to photochemical smog in mice and evaluate if VDD results in epigenetic changes that silence klotho expression. Three-week-old mice will be placed on either a VDD or normal diet for 16 weeks. Mice will either be surgically implanted with biopotential radiotelemeters to continuously measure electrocardiogram (ECG) and heart rate, or will undergo echocardiography (Echo) and whole-body plethysmography (WBP) throughout the diet, before and after smog exposure to track cardiac and ventilatory function, respectively. Mice will then be exposed to either a complex smog mixture or filtered air. ECG will be analyzed for intervals, arrhythmias and heart rate variability (HRV). Second, the DNA methylation state of klotho and gene expression of klotho and TRPA1 will also be assessed. Lastly, we will investigate if TRPA1 modulation by klotho plays a role in VDD-induced worsening of cardiovascular responses to air pollution. The involvement of TRPA1 will be determined by exposing mice to acrolein, which is a TRPA1 agonist. Mice will be treated with recombinant klotho or saline for 3 weeks at the end of the previously described VDD diet regimen to determine if the potentiated effects are blocked. ECG, HRV, Echo and WBP will be done as assessments of function. This project will be the first to characterize the role of VDD in worsening cardiovascular responses to air pollution. This work will also clarify the mechanism by which early-life VDD “sensitizes” the cardiovascular system to air pollution-induced dysfunction.