Characterization of the Role of Histamine in Children with Asthma

组胺在儿童哮喘中的作用特征

• 批准号: 8261088
• 负责人: BRIDGETTE L. JONES
• 金额: $ 12.85万
• 依托单位: CHILDREN'S MERCY HOSP (KANSAS CITY, MO)
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261088
• 关键词: Achievement; Address; Adrenal Cortex Hormones; Adverse effects; Adverse event; Affect; Allergic; Allergic Disease; American; American Lung Association; Antihistamines; Asthma; Atopic Dermatitis; Award; Breathing; Child; Childhood; Chronic Disease; Clinical Pharmacology; Clinics and Hospitals; Collaborations; Complex; Coupled; Cross-Over Studies; Data; Diagnosis; Disease; Double-Blind Method; Drug Exposure; Drug Kinetics; Elements; Extrinsic asthma; Functional disorder; Funding; Future; Generations; Genes; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Health; Heterogeneity; Histamine; Histamine N-Methyltransferase; Histamine Receptor; Histidine Decarboxylase; Hypersensitivity; Immunology; Individual; Institution; Instruction; Interruption; Investigation; Iontophoresis; K-Series Research Career Programs; Knowledge; Lasers; Learning; Life Style; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metabolic Biotransformation; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Phenotype; Placebo Control; Plant Roots; Play; Positioning Attribute; Prevalence; Production; Randomized; Relative (related person); Research; Research Personnel; Role; Schools; Sedation procedure; Signal Pathway; Signal Transduction; Societies; Technical Expertise; Techniques; Testing; Therapeutic; Time; Toxic effect; Training; Variant; base; career; cell type; cohort; design; diamino oxhydrase; experience; gene interaction; improved; inflammatory marker; innovation; interest; mortality; novel strategies; psychosocial; public health relevance; receptor; receptor expression; response; skills; standard care; success; therapeutic evaluation; treatment response

DESCRIPTION (provided by applicant): Asthma, a chronic disease which produces significant morbidity and mortality in children, is a significant health problem to a large segment of society. According to the American Lung Association, approximately 20 million Americans have asthma and prevalence rates continue to rise. In children, rates increased from 3.6% to 5.8% between 1980 to 2003. Despite considerable advances in the diagnosis and treatment of asthma over the past several years, a sizeable portion of patients do not respond to the "core" treatments such as inhaled corticosteroids. Some studies show that up to one-third of children may not respond to inhaled corticosteroid treatment although, inhaled corticosteroids are recommended by experts as the preferred treatment in children with persistent asthma. We are now learning that the underlying pathophysiology of disease is different among patients with asthma therefore; treatments which are beneficial in some patient groups may be not achieve affect in other groups. Antihistamines have been studied in the past for the treatment of asthma. These studies have shown that there may be a beneficial effect of antihistamines in patients with allergic asthma where histamine likely plays a large role in disease and treatment response. However, there is not enough evidence to include these drugs in the standard treatment of asthma. Past studies have not focused on investigating the benefit of antihistamines in well-defined asthma phenotype. In addition, the benefit of earlier investigated antihistamines was hindered due to associated side-effects such as sedation which limit their daily use. We hypothesize that histamine plays a definable, significant role in disease pathogenesis and treatment response in children with allergic asthma. We plan to test this overall hypothesis through two specific aims. The first aim will characterize the relative contribution of histamine in allergic vs. non-allergic asthma. This aim will be accomplished by comparison of the microvasculature response to histamine in children with allergic asthma and children with non-allergic asthma, measured by histamine iontophoresis with laser Doppler (HILD) monitoring, to determine potential phenotype-associated differences in the pharmacodynamic response to histamine. We will also investigate the role of genetic variation in the observed differences in HILD between the two groups. The second aim will characterize the pharmacodynamic response to antihistamines via HILD in children with an exaggerated histamine response compared to children with a low histamine response. This aim will be accomplished through conduct of a randomized, double-blind, placebo-controlled cross-over trial of levocetirizine (LCT) in the two groups (high histamine and low histamine) and observing the difference in antihistamine pharmacodynamics in the two groups. We will also investigate the effect of pharmacokinetic variation and genetic variation in the histamine pathway on the observed pharmacodynamic drug response. I, along with my mentors, have designed this proposal to be an intensive educational and research experience that will allow me to earn key skills to become an independent translational investigator combining knowledge and expertise in allergy/asthma/immunology and pediatric clinical pharmacology to conduct research which improves the therapeutic outcomes in children with asthma. To this end, Children's Mercy Hospitals and Clinics provide an ideal setting for my training. I have assembled a core group of individuals who will serve as the "mentoring team" for the duration of the proposed K23 award. Each of these highly accomplished individuals possesses complementary expertise pertaining to my research and career goal(s) and extensive experience as successful well-funded independent investigators and mentors. Through mentorship and collaboration I will receive exceptional training in pediatric clinical pharmacology research focused on characterization of disease and treatment response in children with asthma. Receipt of this 5-year career development award will provide me with: (1) valuable and necessary training and tutelage from accomplished researchers, (2) supported time to gain targeted, relevant didactic instruction specific to my research and career goals, (3) time for practical scientific experience along with acquisition of specific expertise and technical skills required to successfully pursue my research interests, and (4) support and protected research time necessary to facilitate and insure my transition to an independent investigator. Coupled with continued and significant support from my institution, a K23 grant from NHLBI would position me for future success through the achievements that will be possible during the period of the award. PUBLIC HEALTH RELEVANCE: These proposed investigations will fill critical gaps in knowledge concerning the role of histamine in asthma and treatment response in addition to establishing an innovative investigational paradigm for characterization of disease and therapeutic response.

描述（由申请人提供）：哮喘是一种慢性疾病，在儿童中产生明显的发病率和死亡率，这对大部分社会来说是一个重大的健康问题。根据美国肺部协会的数据，大约2000万美国人患有哮喘，患病率持续上升。在儿童中，比率从1980年到2003年之间从3.6％增加到5.8％。尽管在过去几年中诊断和治疗哮喘的诊断和治疗方面取得了很大进步，但很大一部分患者对“核心”治疗（例如吸入皮质类固醇）没有反应。一些研究表明，多达三分之一的儿童可能无法对吸入的皮质类固醇治疗反应，尽管专家建议吸入的皮质类固醇是对持续性哮喘的儿童的首选治疗方法。我们现在了解到，哮喘患者的疾病的潜在病理生理学是不同的。在某些患者组中有益的治疗可能无法在其他群体中获得影响。过去已经研究了抗组胺药以治疗哮喘。这些研究表明，抗组胺药在过敏性哮喘患者中可能具有有益作用，其中组胺可能在疾病和治疗反应中起着很大作用。但是，没有足够的证据将这些药物包括在哮喘的标准治疗中。过去的研究并未集中于研究抗组胺药在定义明确的哮喘表型中的好处。此外，由于相关的副作用（例如镇静），较早研究的抗组胺药的益处受到阻碍。我们假设组胺在过敏性哮喘儿童中在疾病发病机理和治疗反应中起着可确定的重要作用。我们计划通过两个具体目标来检验这一总体假设。第一个目标将表征组胺在过敏性哮喘中的相对贡献。该目标将通过比较过敏性哮喘儿童的微血管对组胺的反应和非过敏性哮喘的儿童，通过组胺离子噬菌体与激光多普勒（HILD）监测测量，以确定药物学对组胺的药物学反应中潜在的表型相关差异。我们还将研究遗传变异在两组之间观察到的HILD差异中的作用。与组胺反应较低的儿童相比，第二个目标将通过HILD来表征通过HILD对抗组胺药对抗组胺药的药效反应。这一目标将通过在两组（高组胺和低组胺）中进行左旋乙醇（LCT）的随机，双盲，安慰剂对照的交叉试验来实现，并观察两组抗组胺药的差异。我们还将研究组胺途径中的药代动力学变异和遗传变异对观察到的药效药物药物反应的影响。我与我的导师一起设计了这一建议，是一项深入的教育和研究经验，使我能够赢得关键技能，成为一名独立的转化研究者，结合了过敏/哮喘/免疫学和儿科临床药理学的知识和专业知识，从而改善了哮喘儿童的治疗外观。为此，儿童慈悲医院和诊所为我的培训提供了理想的环境。在拟议的K23奖项期间，我组建了一个核心群体，他们将担任“指导团队”。这些高度成就的个人中的每一个都具有与我的研究和职业目标有关的互补专业知识，以及作为成功资助的独立调查员和导师的丰富经验。通过指导和协作，我将获得针对哮喘儿童疾病和治疗反应的儿科临床药理学研究的卓越培训。获得这项为期5年职业发展奖的收到将为我提供：（1）有价值的培训和教导，（2）获得有针对性的，相关的与我的研究和职业目标的有针对性的，相关的教学指令，（3）实践科学经验的时间，以及我的研究兴趣和跨性别的研究所需的特定专业技能，并获得了我的研究兴趣，并获得了我的研究兴趣，并获得了我的研究兴趣，并获得了我的研究兴趣，并获得了我的研究和实用的启用（4），并（4）调查员。再加上我机构的持续和重大支持，NHLBI的K23赠款将通过在奖励期间实现的成就为我的未来成功定位。 公共卫生相关性：这些拟议的调查还将填补有关组胺在哮喘和治疗反应中作用的关键空白，此外还建立了创新的研究范式来表征疾病和治疗反应。