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: 8463603
• 负责人: BRIDGETTE L. JONES
• 金额: $ 12.83万
• 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/8463603
• 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.

描述(申请人提供)：哮喘是一种慢性疾病，会导致儿童的严重发病率和死亡率，对社会的很大一部分人来说是一个严重的健康问题。根据美国肺脏协会的数据，大约有2000万美国人患有哮喘，而且患病率还在继续上升。在儿童中，这一比例从1980年的3.6%上升到2003年的5.8%。尽管在过去的几年里，哮喘的诊断和治疗取得了长足的进步，但相当大一部分患者对吸入皮质类固醇等“核心”治疗没有反应。一些研究表明，多达三分之一的儿童可能对吸入皮质类固醇治疗没有反应，尽管专家建议吸入皮质类固醇作为持续性哮喘儿童的首选治疗方法。我们现在了解到，哮喘患者疾病的基本病理生理学是不同的，因此，对某些患者组有益的治疗可能在其他组不起作用。过去，抗组胺药物曾被研究用于治疗哮喘。这些研究表明，抗组胺药物对过敏性哮喘患者可能有有益的影响，组胺可能在疾病和治疗反应中发挥重要作用。然而，没有足够的证据将这些药物纳入哮喘的标准治疗。过去的研究没有集中于研究抗组胺药物在明确的哮喘表型中的益处。此外，由于镇静等相关副作用限制了抗组胺药物的日常使用，早期研究的抗组胺药物的益处受到了阻碍。我们假设，组胺在过敏性哮喘儿童的疾病发病机制和治疗反应中起着明确的、重要的作用。我们计划通过两个具体目标来检验这一总体假设。第一个目标是确定组胺在过敏性哮喘和非过敏性哮喘中的相对作用。这一目标将通过比较过敏性哮喘儿童和非过敏性哮喘儿童对组胺的微血管反应来实现，组胺离子导入和激光多普勒(HILD)监测测量了这些反应，以确定组胺药效反应中与表型相关的潜在差异。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。第二个目标将描述组胺反应过度的儿童与低组胺反应的儿童相比，通过HILD对抗组胺药物的药效学反应。这一目标将通过在两组(高组胺和低组胺)中进行左西替利嗪(LCT)的随机、双盲、安慰剂控制的交叉试验来实现，并观察两组抗组胺药物药效学的差异。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反应的影响。我和我的导师们将这项建议设计为一种密集的教育和研究经验，使我能够学习关键技能，成为一名独立的翻译调查员，将过敏/哮喘/免疫学和儿科临床药理学的知识和专业知识结合起来，进行研究，以改善哮喘儿童的治疗结果。为此，儿童慈悲医院和诊所为我的培训提供了理想的环境。我已经组建了一个核心小组，他们将在拟议的K23奖项期间担任“指导团队”。这些非常有成就的人中的每一个都拥有与我的研究和职业目标(S)相关的互补专业知识，以及作为成功的、资金雄厚的独立调查人员和导师的丰富经验。通过指导和合作，我将接受儿科临床药理学研究方面的特殊培训，重点是哮喘儿童的疾病特征和治疗反应。获得这个为期5年的职业发展奖将为我提供：(1)来自有成就的研究人员的宝贵和必要的培训和指导，(2)有时间获得针对我的研究和职业目标的有针对性的、相关的教学指导，(3)有时间获得实际的科学经验，以及获得成功追求我的研究兴趣所需的特定专业知识和技术技能，以及(4)支持和保护我的研究时间，以促进和确保我向独立研究人员的过渡。再加上来自我的机构的持续和重要的支持，来自NHLBI的K23赠款将使我能够通过在获奖期间可能取得的成就，为未来的成功做好准备。