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.
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.
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