Mechanisms of Eosinophilic Inflammation in Human Asthma

  • Kita, Hirohito (PI)
  • O'Grady, Scott M. (PI)
  • Gleich, Gerald (PI)
  • O'Grady, Scott M. (PI)
  • Wylam, Mark (PI)
  • O'Grady, Scott M. (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Bronchial asthma is characterized
by episodic exacerbations of airflow limitation, bronchial hyperreactivity and
airway inflammation. Eosinophilic infiltration in the airways is common in
asthma even in mild, stable, or newly diagnosed asthma. Studies suggest a
strong correlation between airway eosinophilia and disease severity in human
asthma. Our Program Project will elucidate the immunologic and cellular
mechanisms responsible for persistent eosinophilic airway inflammation and the
subsequent development of physiologic and pathologic abnormalities in the
airways of patients with asthma; at present these mechanisms are poorly
understood. The combined resources of this Asthma and Allergic Diseases
Research Center (AADRC) provide a unique opportunity to conduct a coordinated
set of interdisciplinary research projects focused on understanding the
mechanisms of eosinophilic inflammation in human asthma. The first project
will investigate post-receptor signaling pathways that control eosinophil
degranulation and granule protein toxicity with a specific focus on calcium
mobilization and protein kinase C (PKC) activation. The project uses
biochemical, pharmacological, and electrophysiological approaches to elucidate
the mechanisms of actin rearrangement and granule acidification, which are
critical events in the degranulation process of human eosinophils. The second
project will investigate how the eosinophil?s release of granule proteins
leads to airway narrowing and bronchial hyperreactivity in patients with
asthma. The project addresses the mechanisms by which eosinophil major basic
protein (MBP) alters contractile responses of human airway smooth muscle by
examining two cellular targets for MBP in the airways: epithelia cells and
smooth muscle cells. The third project will investigate why eosinophilic
airway inflammation persists in patients who do not have immunoglobulin E
(IgE) antibodies to exogenous antigens, namely "intrinsic" asthma. It tests
the hypothesis that enhanced immune responses to fungi in human airways and
subsequent production of eosinophil-active cytokines, such as interleukin
(IL)-5 and interferon (IFN)-gamma, are involved. The project also examines
how eosinophil degranulation in the airways leads to exacerbation of asthma in
patients. The Administrative Core will provide administrative services and
support for the collaborative efforts among the projects. Finally, the
Eosinophil Granule Protein Core is an essential resource that provides unique
reagents and technical service to analyze eosinophilic inflammation.
Altogether, these projects may elaborate the pathogenic and pathophysiologic
mechanisms of human bronchial asthma and may improve the diagnosis and
therapeutic interventions in the management of patients suffering form asthma.
StatusFinished
Effective start/end date9/10/016/30/07

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)