ADENOSINE RECEPTORS AS THERAPEUTIC TARGETS FOR CHRONIC RHINOSINUSITIS
Lloyd Stephen
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 1R21AI096139-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: Chronic rhinosinusitis (CRS) is a very common upper airway disease affecting more than 31 million Americans. Current therapeutic strategies for CRS include both medical and surgical treatments; one major goal of these treatments is to improve the nasal mucociliary clearance (MCC) function in CRS patients, as this may reverse the diseased sinonasal mucosa to achieve physiological recovery. Adenosine is a ubiquitous nucleoside normally present in the airway lumen and interstitium. Previous in vitro studies have shown that adenosine is the major regulator for nasal airway surface liquid homeostasis. It can also increase cilia beating frequency of cultured human nasal epithelium. In our preliminary in vivo studies, a potent effect of adenosine, but not ATP, to accelerate nasal MCC was also observed. These findings indicate that adenosine and its receptors may be of great therapeutic value for CRS by speeding up nasal MCC. In addition to regulating MCC, adenosine has also been shown to elicit both anti- and pro-inflammatory effects. Although previous studies in the lower airways have revealed that adenosine enhances inflammation, our preliminary studies have shown that adenosine is not pro-inflammatory in the nose and sinuses. Based on all of these findings, we hypothesize that adenosine is the key factor to enhance the nasal MCC in vivo (Aim 1) and its anti-inflammatory actions will attenuate the development of CRS (Aim 2). The effect of adenosine on nasal MCC will be tested in vivo at both healthy and inflamed nose and sinuses. The underlying mechanisms will be determined at both in vivo and in vitro levels. The role of adenosine and adenosine receptors in CRS development, progression, and resolution will also be examined. We believe that the completion of this translational project will lead to a novel therapeutic strategy for CRS. It will also be of great significance to enhancing our knowledge of adenosine airway biology and re-evaluating the unified airway theory. Chronic rhinosinusitis (CRS) is a very common inflammatory disease in the nose and sinuses. Currently, both medical and surgical therapies are used for CRS patients; however, many patients still present with persistent inflammation even after aggressive treatment. In the proposed studies, we will examine the role of adenosine, a common mediator in human body, and its receptors, in CRS development, and explore the therapeutic value of targeting adenosine receptors for the treatment of CRS
Keywords: Adenosine; adenosine deaminase; Affect; Age; Agonist; airway epithelium; airway surface liquid; American; Anti-inflammatory; Anti-Inflammatory Agents; Asthma; Attenuated; base; Biological; Biology; Blood; Breathing; Cessation of life; Chronic; Chronic Obstructive Airway Disease; chronic rhinosinusitis; Cilia; Clinical Data; Complement; Complex; Coughing; Coupled; Defense Mechanisms; Development; Disease; Dissection; effective therapy; Enzymes; Epithelial Cells; Frequencies (time pattern); Functional disorder; Funding; Genetic; Goals; Homeostasis; Host Defense Mechanism; Human; Human body; Hypersensitivity; Immunology; improved; In Vitro; in vivo; Inflammation; Inflammatory; Inflammatory Response; Interdisciplinary Study; Investigation; Knowledge; Lead; Lung Inflammation; Mediator of activation protein; Medical; Medicine; Methods; Mucociliary Clearance; Mucous body substance; Mucous Membrane; Mus; Nasal cavity; Nasal Epithelium; Nervous system structure; Neurosecretory Systems; new therapeutic target; Nose; novel therapeutics; Nucleosides; Nucleotides; Operative Surgical Procedures; Otolaryngology; Oxygen; pathogen; Pathogenesis; Patients; Physiological; Physiology; pre-clinical; Primary Ciliary Dyskinesias; Process; programs; Purinergic P1 Receptors; receptor; Recovery; Regulation; Research; Resolution; Respiratory Failure; Role; Scanning; shear stress; Signal Pathway; Sinus; Sneezing; Speed (motion); Structure of mucous membrane of nose; Testing; theories; Therapeutic; therapeutic target; United States; Work
Relevance: Chronic rhinosinusitis (CRS) is a very common inflammatory disease in the nose and sinuses. Currently, both medical and surgical therapies are used for CRS patients; however, many patients still present with persistent inflammation even after aggressive treatment. In the proposed studies, we will examine the role of adenosine, a common mediator in human body, and its receptors, in CRS development, and explore the therapeutic value of targeting adenosine receptors for the treatment of CRS
Project start date: 2012-02-01
Project end date: 2014-01-31
Budget start date: 1-FEB-2012
Budget end date: 31-JAN-2013
1R21AI096139-01A1 (2012): $185000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Lloyd Stephen
Lloyd Stephen, Assistant Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Abstract: The long-term objective of this core is to provide investigators interested in environmental lung disease the resources and technical expertise required to conduct in vivo mechanistic studies in mice. The following core services will be provided 1) importation and exportation of mice, 2) breeding of wild type mice for mechanistic studies, 3) breeding and genotying of genetically manipulated mouse lines for use in mechanistic studies, 4) development of allergic mice using both acute and chronic sensitization/challenge protocols, 5) exposure of animals to model environmental pollutants, 6) treatment interventions to test the efficacy, toxicity, and mechanisms of action of novel therapies, and 7) physiological phenotyping of mice after the induction of environmental lung disease for evaluation of airway resistance, compliance, and airway hyperresponsiveness to methacholine. This core supports the mission of NIAID to study genetic and environmental interactions as they relate to environmental lung disease. Mechanistic studies in animals, particularly the use of genetically manipulated mice, is essential for the development of new therapies to improve public health
Keywords: Acute; airway epithelium infalmmation; airway hyper-reactivity; Airway Hyper-responsiveness; airway hyperreactivity; airway hyperresponsiveness; airway inflammation; airway remodeling; Airway Resistance; Allergens; Allergic; Allergic inflammation; Animal Model; Animal Models and Related Studies; Animals; Antigens; Asthma; ATGN; Biochemical; Biology; Blood Serum; Body Tissues; Breeding; Bronchial Asthma; Bronchial Lavage Fluid; Cell Count; Cell Number; Chronic; Computers; Data; design; designing; Development; Disease; Disease model; disease/disorder; Disorder; disorder model; efficacy testing; embryonic stem cell; Endotoxins; environmental agent; Environmental Pollutants; Eosinophilia; ES cell; Evaluation; Exposure to; Formalin; Freezing; gene product; Genes; Genetic; genetic technology; Goals; Harvest; Histology; Human; human disease; Human, General; Immunobiology; immunogen; Immunophysiology; improved; in vivo; Inbreeding; Individual; interest; Intervention; Intervention Strategies; interventional strategy; Investigators; Laboratory mice; Lavage Fluids, Alveolar; Lipids; Lung; Lung diseases; lung disorder; Lung Inflammation; Lung Lavage Fluid; Lung Parenchyma; Lung Tissue; Mammals, Mice; Man (Taxonomy); Man, Modern; Measurable; Measurement; Measures; Mechanics; meetings; methacholine; Mice; Mission; model organism; Modeling; molecular phenotype; mouse model; Mouse Strains; mRNA Expression; mucous; Mucous body substance; Mucus; Murine; Mus; National Institute of Allergy and Infectious Disease; NIAID; novel; Obstruction; Palsy; Paralysed; paralysis; paralytic; Pathogenesis; Peripheral; Phase; Phenotype; Physiologic; Physiological; Plegia; Production; protein expression; Proteins; Protocol; Protocols documentation; Public Health; public health medicine (field); pulmonary; Pulmonary Diseases; Pulmonary Disorder; Research Personnel; Research Resources; Researchers; Resistance; resistant; Resources; Respiratory Disease; Respiratory Disorder; Respiratory System Disease; Respiratory System Disorder; Respiratory System, Lung; response; Role; Serum; Services; Signal Pathway; social role; stem cell of embryonic origin; Structure of parenchyma of lung; Technical Expertise; Testing; Tissue Banks; Tissue Collection; Tissue/Specimen Collection; Tissues; Toxic effect; Toxicities; transgenic; Transgenic Organisms; Ventilator; Wild Type Mouse; Work
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5U19AI077437-04_8458 (2011): $230379
ROLE OF ADENOSINE IN ALLERGIC LUNG DISEASE
Lloyd Stephen, Assistant Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 5R01HL071802-08 from National Heart, Lung, And Blood Institute
Abstract: Elevated adenosine levels in the lungs and exhaled breath of asthmatics, with further increases following antigen challenge, suggests that this ubiquitous mediator may contribute to the pathophysiology of asthma. Many of the effects of adenosine in the asthmatic lung are mast cell-dependent. Adenosine has both pro- and anti-inflammatory effects on mast cells, due to the expression of multiple adenosine receptors on the cell surface, each capable of activating very different intracellular signaling pathways. In this proposal we will test the hypothesis that both pro- and anti-inflammatory signals are transmitted to the mast cell by adenosine via the activation of distinct cell-surface receptors, and that engagement of these receptors by adenosine influences AHR, inflammatory cell influx, and airway remodeling. In aim 1 we will investigate the pro- inflammatory role of A3 receptors on mast cells in AHR, airway inflammation, and remodeling. In aim 2 we will investigate the capacity of agonist-induced activation of Gs-coupled adenosine receptors to limit AHR, airway inflammation, and remodeling. In aim 3 we will investigate constitutive activity of the A2B receptor. For all aims we will conduct in vitro experiments with human mast cells as well as mechanistic in vivo experiments using a series of models lacking adenosine receptors on mast cells. Completion of these aims will define pro- vs. anti-inflammatory signaling pathways on the mast cell, and identify the mechanisms by which adenosine- induced mast cell activation contributes to the cardinal features of asthma. PUBLIC HEALTH RELEVANCE. Asthma is a common chronic disease affecting approximately 10% of people in the United States. A better understanding of the inflammatory mediators involved in this disease, such as adenosine, will help identify new avenues of therapy, leading to better treatments for asthma
Keywords: Adenosine; Affect; Agonist; airway hyperresponsiveness; airway inflammation; airway remodeling; Allergens; Allergic; allergic airway inflammation; Anti-inflammatory; Anti-Inflammatory Agents; antigen challenge; Antigens; Asthma; asthmatic airway; Bone Marrow; Bronchoconstriction; Cell physiology; Cell surface; Cell Surface Receptors; Cells; Chronic Disease; clinical application; Complex; Coupled; desensitization; design; Development; Disease; Exhalation; Functional disorder; Funding; G-Protein-Coupled Receptors; Gene Silencing; Genetically Modified Animals; Goals; Health; Homeostasis; Human; In Vitro; in vivo; Inflammation; Inflammation Mediators; Inflammatory; Ligands; Lung; Lung diseases; mast cell; Mediating; Mediator of activation protein; Modeling; Mus; novel therapeutic intervention; Pathogenesis; Pathway interactions; Play; programs; Protocols documentation; Purinergic P1 Receptors; receptor; receptor coupling; receptor function; Receptor Signaling; Research; research study; Role; Series; Signal Pathway; Signal Transduction; small hairpin RNA; Sputum; Testing; therapeutic target; Transfection; Translations; Umbilical Cord Blood; United States
Project start date: 2002-12-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01HL071802-08 (2011): $370000