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

Klotho 和 TRPA1 在维生素 D 缺乏和空气污染引起的心肺功能障碍中的作用

• 批准号: 9471224
• 负责人: Kimberly Stratford
• 金额: $ 0.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9471224
• 关键词: Acrolein; Address; Adult; Affect; Agonist; Air Pollutants; Air Pollution; Animals; Arrhythmia; Blood; Breathing; Cardiac; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cations; Chronic; Complex; DNA Methylation; Data; Development; Diet; Echocardiography; Electrocardiogram; Environmental Pollutants; Epidemiology; Epigenetic Process; Exposure to; Functional disorder; Gene Expression; Gene Targeting; Genetic Transcription; Goals; Health; Heart; Heart Rate; High-Throughput RNA Sequencing; Human; Hypermethylation; Hypertension; Implant; Irritants; Knowledge; Life; Link; Malnutrition; Measures; Mechanics; Mediating; Methylation; MicroRNAs; Micronutrients; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial dysfunction; Operative Surgical Procedures; Particulate Matter; Pattern; Physiological; Physiology; Play; Predisposition; Production; Proteins; Public Health; Recombinants; Regimen; Role; Saline; Smog; Structure of parenchyma of lung; Technology; Testing; Tissues; Toxic effect; Vitamin D; Vitamin D Deficiency; Weaning; Whole Body Plethysmography; Work; adverse outcome; air filter; anti aging; cardiovascular disorder risk; environmental stressor; genome-wide; heart function; heart rate variability; improved; mortality; nutrition; prenatal exposure; promoter; receptor; response; stressor; toxicant; Acrolein; Address; Adult; Affect; Agonist; Air Pollutants; Air Pollution; Animals; Arrhythmia; Blood; Breathing; Cardiac; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cations; Chronic; Complex; DNA Methylation; Data; Development; Diet; Echocardiography; Electrocardiogram; Environmental Pollutants; Epidemiology; Epigenetic Process; Exposure to; Functional disorder; Gene Expression; Gene Targeting; Genetic Transcription; Goals; Health; Heart; Heart Rate; High-Throughput RNA Sequencing; Human; Hypermethylation; Hypertension; Implant; Irritants; Knowledge; Life; Link; Malnutrition; Measures; Mechanics; Mediating; Methylation; MicroRNAs; Micronutrients; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial dysfunction; Operative Surgical Procedures; Particulate Matter; Pattern; Physiological; Physiology; Play; Predisposition; Production; Proteins; Public Health; Recombinants; Regimen; Role; Saline; Smog; Structure of parenchyma of lung; Technology; Testing; Tissues; Toxic effect; Vitamin D; Vitamin D Deficiency; Weaning; Whole Body Plethysmography; Work; adverse outcome; air filter; anti aging; cardiovascular disorder risk; environmental stressor; genome-wide; heart function; heart rate variability; improved; mortality; nutrition; prenatal exposure; promoter; receptor; response; stressor; toxicant

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.

项目摘要 人类研究表明，空气污染与心血管发病率有关 营养在修饰这种敏感性中的作用尚不清楚。维生素D缺乏症（VDD）具有 成为公共卫生的关注以及与其他互动的不利后果 压力源需要被理解。 VDD与低水平的抗衰老蛋白相关 在窦功能中起着关键作用。那我假设VDD恶化了心血管 由于较低的klotho引起的空气污染暴露，尤其是心律不齐的功能障碍 表达。我们以前的数据表明，空气污染引起的心血管影响是 由瞬态接收器电势（TRP）刺激性通道介导的，特别是TRPA1，是 由克洛托（Klotho）监管。那我感到惊讶的是，VDD对这些影响的后悔是由于Klotho- 诱导TRPA1函数的变化。首先，我将确定早期生命VDD对 对小鼠光化学烟雾的心血管反应，并评估VDD是否导致 表观遗传变化使klotho表达沉默。三周大的小鼠将被放在任何一个 VDD或正常饮食持续16周。小鼠要么用生物电势植入手术 radiotelemeter可连续测量心电图（ECG）和心率，或者将 整个饮食中都会经历超声心动图（ECHO）和全身杂质图（WBP）， 烟雾之前和之后分别跟踪心脏和通气功能。老鼠会 然后暴露于复杂的烟雾混合物或过滤空气中。 ECG将分析 间隔，心律不齐和心率变异性（HRV）。其次，DNA甲基化状态 Klotho和Klotho和TRPA1的基因表达也将进行评估。最后，我们会的 调查Klotho调制的TRPA1是否在VDD引起的担忧中起作用 心血管对空气污染的反应。 TRPA1的参与将由 将小鼠暴露于丙烯醛中，这是trpa1激动剂。小鼠将用重组治疗 在先前描述的VDD饮食方案结束时，Klotho或盐水持续了3周 确定是否阻塞了潜在的效果。 ECG，HRV，Echo和WBP将完成 功能评估。该项目将是第一个表征VDD在 对空气污染的心血管反应恶化。这项工作还将阐明机制 通过其中，早期寿命VDD将心血管系统“敏感”到空气污染引起的 功能障碍。