ASTHMA CLINICAL RESEARCH NETWORK (ACRN)
Richard J Martin, Professor & Director
National Jewish Medical & Res Ctr
denver, Co 80206
Grant 2U10HL051834-06 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: This application proposes to continue the participation of investigators at National Jewish Medical and Research Center in an interactive network of six centers, the Asthma Clinical Research Network (ACRN) in conducting studies of novel therapies for asthma and in disseminating findings to the practicing community. The need for such a network was suggested by increases in the mortality, morbidity, prevalence, and costs of asthma, by research studies showing that asthma is linked to airway inflammation, and by the accelerating rate of development of potentially effective, but also potentially costly treatments. Defining the place of these new therapies was seen as requiring collaborative, multi-center studies examining subjects reflecting the diversity of the U.S. population. In its first 5 years, the ACRN established an interactive infrastructure and added a research site at Harlem Hospital, New York, which serves a predominantly minority population. The ACRN completed and published trials of the effects of regular use of a Beta- agonist in mild asthma ("BAGS") and of the efficacy of colchicine as an alternate to an inhaled corticosteroid (ICS) in moderate asthma. It is now conducting trials comparing a long-acting Beta-agonist, an ICS, and the combination of the two in moderate to severe asthma. We are about to start a 5th study to establish doses of different ICS with equivalent effects on cortisol secretion. These studies have been presented at meetings of the ATS, ACCP, and AAAAI, as have 10-12 ancillary studies analyzing the performance of clinical research. The ACRN has also reported its findings from subgroup analysis of the "BAGS" study that subjects with different genotypes for the Beta-adrenergic receptor are differently affected by regular use of albuterol. This application proposes continued participation of the National Jewish Asthma Clinical Research group in the multicentered, collaborative trials of the ACRN. The studies proposed include a comparison of the clinical efficacy of doses of different inhaled corticosteroids with equal systemic effects, a prospective study of regular use of an inhaled Beta-agonist in subjects stratified by genotype for the Beta-adrenergic receptor, a study of the efficacy of a leukotriene pathway antagonist in enabling reduction or elimination of inhaled corticosteroid therapy in subjects with mild or moderate persistent asthma, and other studies illustrated briefly in this application, but modified or replaced by the ACRN Steering Committee in response to new information or the release of new forms of therapy
Keywords: asthma, beta adrenergic agent, corticosteroid, human therapy evaluation, information dissemination, respiratory disorder chemotherapy antiinflammatory agent, bronchodilator, clinical trial, colchicine, cooperative study, dosage, enzyme inhibitor, inhalation drug administration, leukotriene, lipoxygenase, patient care management, pharmacogenetics clinical research, human subject
Project start date: 1993-09-30
Project end date: 2003-08-31
2U10HL051834-06 (1998): $745000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Richard J Martin
STEROID AND TARGET CELL FOCUS IN THE TREATMENT OF ASTHMA
Richard J Martin, Professor & Director
National Jewish Medical And Res Ctr Denver, Co 80206
Grant 5U10HL051834-03 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: While there has been a tremendous advancement in the understanding of the pathophysiology of asthma, both the prevalence and mortality from this disease are increasing. Although asthma is a syndrome comprised of complex interactions of events both externally and internally, airways inflammation plays a prominent role in the overall course. Thus, the specific aims of the two projects presented in this grant focus on interrupting the inflammatory cascade in asthmatic patients. Inhaled glucocorticoids are now suggested to be first line medications in asthma treatment, yet there is not a clear standardized clinical model that can compare one type of inhaled glucocorticoid to another or varying doses to each other. The specific aim of the first project is to develop a standardized clinical model for inhaled glucocorticoid testing by introducing a "prednisone milligram equivalent" scale. In doing so, one inhaled agent can be tested against another in regard to beneficial and detrimental effects. Additionally, dosing schedules of different strengths and times can also be adequately compared. This will allow objective measures to be followed by clinicians, regulatory boards and the pharmaceutical industry, thereby improving patient care for all age groups. The second project focuses on "target cell - specific drugs", initially separately and then in combination. The four novel agents to be investigated are inhaled interleukin-1 receptor antagonist (macrophage), inhaled heparin (eosinophil, mast cell), oral cyclosporin (T-lymphocyte) and erythromycin (neutrophil). Once the individual target cell medication has been evaluated, then the most promising medications will be selected for combination trials. It is postulated that combination low dose regimens will provide comprehensive control of airway inflammation while minimizing adverse effects in moderate to severe asthmatic patients. Using low dose combination regimens may replace the necessity of using oral glucocorticoids in certain asthmatic patients and thereby eliminating the severe glucocorticoid complications that are commonly seen in these patients. Both projects will also use bronchoalveolar lavage/biopsy and/or plasma markers of inflammation to identify the modes of action of these agents; also to determine if these markers can be used to measure the anti-inflammatory effect of these therapeutic interventions. The Asthma Clinical Research Network will provide the opportunity to address these as well as other critical therapeutic issues in the management of asthma.
Keywords: asthma, bronchodilator, human therapy evaluation, respiratory disorder chemotherapy, clinical trial, cooperative study, cyclosporine, diagnostic respiratory lavage, dosage, drug adverse effect, erythromycin, glucocorticoid, heparin, interleukin 1, patient care management, prednisolone, respiratory therapy, human subject
Project start date: 1993-09-30
Project end date: 1998-08-31
5U10HL051834-03 (1995): $624723
5U10HL051834-02 (1994): $615378
5U10HL051834-05 (1997): $666238
CLINICAL CENTERS FOR THE NHLBI ASTHMA NETWORK (ASTHMANET)
Richard J Martin
National Jewish Health, 1400 Jackson Street, Denver, Co 80206
Grant 5U10HL098075-02 from National Heart, Lung, And Blood Institute
Abstract: To address new treatment approaches through AsthmaNet, National Jewish Health will contribute expertise under the direction of Drs. Richard Martin and Stanley Szefler along with experienced investigators from the ACRN and CARE Networks, and Dr. Lisa Cicutto as leader in the Education, Training and Career Development Core and the Community Engagement Core of the Colorado Clinical and Translational Sciences Institute. To understand the relationship of asthma, vitamin D deficiency and obesity in adults, we will examine the role of vitamin D supplementation to enhance inhaled corticosteroid (ICS) response. After a run-in period of ICS, based on evidence of vitamin D deficiency and stratified for body mass index, subjects with asthma, ages 18 to 70 years, will be randomized to ICS plus vitamin D or placebo for a 6-month period in a double-blind, parallel, placebo controlled design to evaluate change in asthma control. An associated mechanistic study will examine cellular mechanisms of steroid response related to the MAP kinase-1 pathway. To improve asthma management in young children, we will evaluate three treatments low dose ICS delivered via nebulizer/face mask, low dose ICS via metered dose inhaler/spacer/face mask, or an oral leukotriene antagonist. After a placebo run-in, children with asthma, ages 1 to less than 5 years, will be randomized to one treatment in a double-blind, parallel design for a one-year study period. We will measure symptom control and exacerbations and also determine whether therapy can be individualized based on patient characteristics including biomarkers and genetics. To evaluate a novel treatment strategy, we will examine the role of an omega3/antioxidant nutritional formula on exercise-induced bronchospasm in adolescents, ages 12 to 18 years, using a double-blind, placebo controlled, parallel design over a three month treatment period. We will also implement a Clinical Research Skills Development Core Plan and contribute expertise in quality control of physiological clinical outcomes to develop independent academic clinical investigators in asthma. The National Jewish site will contribute collaborative experience, leadership skills and commitment for recruitment of adults and children to participate in AsthmaNet trials
Keywords: 0-11 years old; 21+ years old; Address; Adolescent; Adolescent Youth; Adrenal Cortex Hormones; Adult; Age; Antioxidants; Aspiration, Respiratory; Asthma; BMI percentile; BMI z-score; Body mass index; Breathing; Bronchial Asthma; Caring; Characteristics; Child; Child Youth; Children (0-21); Clinical; Clinical Investigator; Clinical Research; Clinical Study; Colorado; Communities; Corticoids; Corticosteroids; Development; Dose; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; ERK 2; Exercise-Induced Bronchospasm; Extracellular Signal-Regulated Kinase 2; Genetic; Health; Human, Adult; Human, Child; Inhalation; Inhaling; Inspiration, Respiratory; Institutes; Investigators; Jewish; Jewish, follower of religion; Leadership; Leukotriene Antagonists; Leukotriene Receptor Antagonists; MAP Kinase 1; MAP Kinase 2; MAPK1; MAPK1 Mitogen-Activated Protein Kinase; MAPK2 Mitogen-Activated Protein Kinase; MDI (Inhalers); Measures; Metered Dose Inhaler Device; Metered Dose Inhalers; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 2; National Heart, Lung, and Blood Institute; Nebulizer; Nutritional; Obesity; Oral; Outcome; P42MAPK; PBO; PRKM1; Pathway interactions; Patients; Physiologic; Physiological; Placebo Control; Placebos; Quality Control; Quetelet index; Randomized; Research Personnel; Researchers; Role; Running; Sham Treatment; Site; Steroid Compound; Steroids; Supplementation; Symptoms; Therapeutic Corticosteroid; Training and Education; Translational Research; Translational Research Enterprise; Translational Science; Treatment Period; VIT D; Vitamin D; Vitamin D Deficiency; adiposity; adult human (21+); anti-oxidant; base; biomarker; career development; children; corpulence; corpulency; corpulentia; design; designing; experience; face mask; follower of religion Jewish; improved; inspiration; juvenile; juvenile human; novel; obese; obese people; obese person; obese population; p42 MAP Kinase; p42 MAPK; p42(Mapk) Kinase; p42(Mitogen-Activated Protein Kinase); pathway; randomisation; randomization; randomly assigned; response; sham therapy; skills; social role; translation research enterprise; treatment days; treatment duration; treatment strategy; youngster
Project start date: 2009-09-30
Project end date: 2016-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: RFA-HL-08-010
5U10HL098075-02 (2010): $875082
1U10HL098075-01 (2009): $531882
COLLABORATIVE HOME INFANT MONITORING EVALUATION (CHIME)
Richard J Martin, Professor & Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5M01RR000080-410810 from National Center For Research Resources
Abstract: This protocol is a multicenter collaborative trial of Home Infant Apnea Monitors. These devices are used to monitor breathing and heart rate in infants thought to be at risk for SIDS as well as normal controls. This study will yield extensive descriptive information regarding the efficacy of apnea monitors, their accuracy, and the ability of these devices to detect clinically important events. The follow-up of the infants continues until approximately age 1.5 yrs. The GCRC Psychometrists assist with the developmental assessments.
Keywords: apnea, disease /disorder prevention /control, evaluation /testing, infant human (0-1 year), monitoring device, clinical trial, disease /disorder proneness /risk, heart rate, longitudinal human study, pulmonary respiration, sudden infant death syndrome, clinical research, human subject
Sponsored Links Excellgen http://Excellgen.com
The Effect Of Mycoplasma On Chronic Asthma
Richard J Martin, Department Of Medicine
National Jewish Health
1400 Jackson Street
denver, Co 80206
Grant 5P01HL073907-05 from National Heart, Lung, And Blood Institute IRG: HLBP
Abstract: This Program Project Grant (PPG) will bring together 16 investigators in four Projects and two Cores to continue our work in the area of the link between chronic infection (M. pneumoniae) and chronic asthma. There have been numerous recent publications suggesting that in a subgroup of asthmatics, approximately 50% have an associated atypical bacterial process. Thus, this PPG will focus on the M. pnemoniae-asthma interaction. Project 1 will evaluate the effect of M. pneumoniae on neurogenic inflammation inducing fibroblast proliferation and altering airway structure (remodeling) and function. This will be done using asthmatic airway epithelial cells and tissue. The focus of Project 2 is to examine the interactions of surfactant proteins (SP)-A and -D, the first line airway defense mechanisms and M. pneumoniae. This project will also identify the domains of the protein that are required for the amplification of the inflammatory response. In addition to this in vitro work, in vivo mouse work will determine how the mycoplasma response is modulated by SP-A and SP-D. Project 3 will use a mouse model of a mycoplasma induced chronic "asthma-like" state by the interaction of allergen and infection exposures. This model will be used to understand the development of chronic bronchial hyper-responsiveness and airway remodeling. Project 4 will use an epithelial human cell line to investigate the effects of M. pneumoniae on mast cell function. Each project is complementary and interactive, thus the critical mass of scientists will be able to work at a higher and interactive level through the PPG. The Administrative Core will function as the fulcrum for the projects and the Histopathology and Microbiology Core will serve each project. The goal of understanding the interaction between M. pneumoniae and asthma will be obtained through this PPG and will ultimately give new knowledge to the understanding of asthma pathophysiology and potential future novel therapies
Keywords: Mycoplasma, asthma clinical research, human tissue, laboratory mouse
Project start date: 2004-07-05
Project end date: 2010-03-31
5P01HL073907-05 (2008): $2062314
5P01HL073907-04 (2007): $2052518
5P01HL073907-03 (2006): $2064538
5P01HL073907-02 (2005): $2069051
1P01HL073907-01A1 (2004): $2008225
Innovative Investigations And Therapies For Asthma
Richard J Martin, Department Of Medicine
National Jewish Medical & Res Ctr
denver, Co 80206
Grant 5U10HL074073-05 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: This Asthma Clinical Research Network (ACRN) grant application involves three investigators who have extensive experience in multicenter asthma investigation. The areas of research expertise that will be brought to the ACRN include adult and pediatric investigation, allergy and immunology, pulmonology, pharmacology, chronobiology, steroid and beta-2 agonist receptor knowledge, airway inflammation, morphometrics, infection, physiology, and patient care. The two research protocols are potentially of great importance to the understanding of asthma pathophysiology and patient care. Protocol 1 will determine the link between chronic infection (Mycoplasma pneumoniae and Chlamydia pneumoniae) and chronic asthma. In a pilot study, we have shown that approximately 50% of patients with asthma exhibit evidence of M. pneumoniae or C. pneumoniae in their airways, and respond to treatment with a macrolide antibiotic. However, evaluation and extension of these observations in large multi-center trials are critical, if we are to potentially identify a new asthma phenotype, and thus affect therapy of asthma. Therefore, we propose to evaluate these patients with both a macrolide antibiotic and an inhaled corticosteroid (ICS) in subjects (+) and (-) for these bacteria. As we have been interested in corticosteroid responsiveness for many years, Protocol 2 will evaluate biomarkers to predict ICS responders (good, marginal, and poor) as well as determining why these different responses occur. This protocol is an extension of our own work, and work through ACRN with Denver as the lead center. Additive therapy, long-acting beta-2 agonists and anti-lgE, will be studied to determine if either or both improve responses to ICS. The ability to predict who will and will not respond to corticosteroids and additive therapy will greatly improve our ability to treat asthma effectively
Keywords: Chlamydiaceae, Mycoplasma pneumoniae, asthma, human therapy evaluation, respiratory disorder chemotherapy albuterol, bacteria infection mechanism, bacterial cytopathogenic effect, beta adrenergic receptor, biomarker, bronchodilator, combination chemotherapy, cooperative study, corticosteroid, immunoglobulin E, inflammation, macrolide antibiotic, nitric oxide, phenotype, respiratory pharmacology, tryptase clinical research, human subject, patient oriented research, polymerase chain reaction, spirometry
Project start date: 2003-09-15
Project end date: 2009-07-31
5U10HL074073-05 (2007): $735943
5U10HL074073-04 (2006): $927420
5U10HL074073-03 (2005): $924784
5U10HL074073-02 (2004): $900439
Sponsored Links Excellgen http://Excellgen.com
1U10HL074073-01 (2003): $874215
ASTHMA CLINICAL RESEARCH NETWORK (ACRN)
Richard J Martin, Department Of Medicine
National Jewish Medical And Res Ctr Denver, Co 80206
Grant 5U10HL051834-10 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: This application proposes to continue the participation of investigators at National Jewish Medical and Research Center in an interactive network of six centers, the Asthma Clinical Research Network (ACRN) in conducting studies of novel therapies for asthma and in disseminating findings to the practicing community. The need for such a network was suggested by increases in the mortality, morbidity, prevalence, and costs of asthma, by research studies showing that asthma is linked to airway inflammation, and by the accelerating rate of development of potentially effective, but also potentially costly treatments. Defining the place of these new therapies was seen as requiring collaborative, multi-center studies examining subjects reflecting the diversity of the U.S. population. In its first 5 years, the ACRN established an interactive infrastructure and added a research site at Harlem Hospital, New York, which serves a predominantly minority population. The ACRN completed and published trials of the effects of regular use of a Beta- agonist in mild asthma ("BAGS") and of the efficacy of colchicine as an alternate to an inhaled corticosteroid (ICS) in moderate asthma. It is now conducting trials comparing a long-acting Beta-agonist, an ICS, and the combination of the two in moderate to severe asthma. We are about to start a 5th study to establish doses of different ICS with equivalent effects on cortisol secretion. These studies have been presented at meetings of the ATS, ACCP, and AAAAI, as have 10-12 ancillary studies analyzing the performance of clinical research. The ACRN has also reported its findings from subgroup analysis of the "BAGS" study that subjects with different genotypes for the Beta-adrenergic receptor are differently affected by regular use of albuterol. This application proposes continued participation of the National Jewish Asthma Clinical Research group in the multicentered, collaborative trials of the ACRN. The studies proposed include a comparison of the clinical efficacy of doses of different inhaled corticosteroids with equal systemic effects, a prospective study of regular use of an inhaled Beta-agonist in subjects stratified by genotype for the Beta-adrenergic receptor, a study of the efficacy of a leukotriene pathway antagonist in enabling reduction or elimination of inhaled corticosteroid therapy in subjects with mild or moderate persistent asthma, and other studies illustrated briefly in this application, but modified or replaced by the ACRN Steering Committee in response to new information or the release of new forms of therapy.
Keywords: asthma, beta adrenergic agent, corticosteroid, human therapy evaluation, information dissemination, respiratory disorder chemotherapy, antiinflammatory agent, bronchodilator, clinical trial, colchicine, cooperative study, dosage, enzyme inhibitor, inhalation drug administration, leukotriene, lipoxygenase, patient care management, pharmacogenetics, clinical research, human subject
Project start date: 1993-09-30
Project end date: 2005-08-31
5U10HL051834-10 (2002): $766455
5U10HL051834-09 (2001): $800568
5U10HL051834-08 (2000): $752216
5U10HL051834-07 (1999): $714553
NEURAL REGULATION OF AIRWAYS DURING POSTNATAL MATURATION
Richard J Martin, Professor And Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5R01HL056470-04 from National Heart, Lung, And Blood Institute IRG: ZRG2
Abstract: The tachykinin peptides, substance P (SP) and neurokinin A (NKA), play an important role in enhancing airway smooth muscle contractile responses, and this role is well preserved across species. The objective of this proposal is to characterize developmental changes in tachykinin-mediated airway smooth muscle contraction, identify corresponding changes in tachykinin (NK1 and NK2) receptor function, localize these maturational changes between large airways and lung parenchyma, and examine the role of hyperoxic stress in modulating these phenomena. In the newborn piglet contractile responses to tachykinins are markedly attenuated over the first days of life. This animal model will be employed to test the hypothesis that immature receptor function contributes to the weak tachykinin-mediated physiologic responses observed in early postnatal life, possibly serving to minimize airway constriction and ensure adequate airway caliber at that time. Parallel in vitro studies will be performed on pig trachea and lung parenchyma at 3 postnatal ages to correlate physiologic responses to SP and NKA administration with receptor binding and autoradiography, G protein levels and measurements of phosphoinositide metabolism and intracellular Ca++. Hyperoxic stress, a common pathophysiologic perturbation, increases SP precursor gene expression and SP content in newborn lung, accompanied by an increase in NK1 and NK2 receptor density. The newborn rat model will be employed to test the hypothesis that hyperoxia-induced facilitation of SP content, release and signaling may compromise airway function by enhancing cholinergically- mediated airway contractile responses under these conditions. Physiologic in vitro and in vivo studies will be performed in rats at 2 postnatal ages, and responsiveness to cholinergic agonists compared after hyperoxic and normoxic exposure in the presence and absence of NK1 and NK2 receptor blockade, and after tachykinin depletion with capsaicin. Physiologic studies performed under hyperoxic and normoxic conditions will be combined with measurements of NK1 and NK2 receptor density and function, and the above signaling pathways. Localization of physiologic responses in rat trachea and lung parenchyma will be correlated with mapping of the corresponding receptors via autoradiography. These studies will allow us to characterize pharmacologic and cellular mechanisms underlying site- specific physiologic responses of developing respiratory structures to tachykinin peptides. The corresponding behavior of these phenomena during hyperoxia should delineate possible mechanisms underlying abnormal pulmonary function in diseases such as bronchopulmonary dysplasia.
Keywords: hyperoxia, muscle contraction, neuroregulation, newborn animal, respiratory muscle, tachykinin, G protein, biological signal transduction, calcium, gene expression, infant animal, inositol phosphate, lung, neuropeptide receptor, receptor binding, receptor coupling, respiratory airway pressure, substance K, substance P, trachea, autoradiography, laboratory rat, northern blotting, swine, western blotting
Project start date: 1996-05-03
Project end date: 2000-12-31
5R01HL056470-04 (1999): $307095
5R01HL056470-03 (1998): $304141
5R01HL056470-02 (1997): $294735
Infection And Allergic Asthma: A Murine Model
Richard J Martin, Department Of Medicine
National Jewish Medical & Res Ctr
denver, Co 80206
Grant 5P01HL073907-050003 from National Heart, Lung, And Blood Institute IRG: HLBP
Abstract: The overall objective of the proposed research for this project is to determine how a respiratory infection (M. pneumoniae) following an allergen challenge propagates chronic bronchial hyper-responsiveness and airway remodeling. Additionally, to determine if acute elimination or blockade of the infective process prevents a chronic "asthma-like" state from developing even with continued allergen challenge. The knowledge gained from this murine model will help in the understanding of the interaction between allergen and infection in regard to chronic inflammatory changes producing airway remodeling and sustained bronchial hyperresponsiveness. Additionally, the model will increase our understanding of how acute interventions altering the effect of an infection can alter the development of chronic bronchial hyperresponsiveness and airway remodeling. Furthermore the Th-1, Th-2 cytokine responses as well as neurogenic inflammatory responses that are involved in this chronic model of asthma will be determined. This information can then be used to design studies in human asthmatic subjects to determine if M. pneumoniae results in a different asthma phenotype that warrants new therapeutic approaches. Thus, the specific aims of this project are Specific Aim 1. To determine the difference in the severity of chronic bronchial hyperresponsiveness between repeated allergen challenges alone and the interaction between allergen and infection. Specific Aim 2. To further evaluate the mechanisms involved in the production of chronic bronchial hyperresponsiveness and airway remodeling. This will be done by blockade or elimination of M. pneumoniae acutely and delineating the effects chronically. Interventions will include innate immunity, surfactant proteins A and D; blocking the ability of mycoplasma to adhere to airway tissue by inhaled corticosteroids; the combination of surfactant proteins and corticosteroids; and acute elimination of the infection by an antibiotic. Specific Aim 3. To determine how acutely altering neurogenic inflammatory responses may change the chronic aspect, i.e., bronchial hyperresponsiveness and airway remodeling. BALB/c mice will be used in this project. We have demonstrated that these mice increase bronchial hyperresponsiveness and airway inflammation following an M. pneumoniae respiratory infection. This is associated with decreased Th-1 cytokine expression. Additionally, we have shown that these mice have a marked increase in bronchial hyperresponsiveness, inflammation, and airway obstruction if the mycoplasma infection follows allergen sensitization and challenge. Therefore it is a proven model to evaluate the specific aims stated above
Keywords: Mycoplasma pneumoniae, allergen, asthma, bacteria infection mechanism, mycoplasmal pneumonia T lymphocyte, cellular immunity, corticosteroid, disease /disorder model, hypersensitivity, immunoglobulin E, immunoglobulin G enzyme linked immunosorbent assay, flow cytometry, histology, laboratory mouse, polymerase chain reaction
Sponsored Links Excellgen http://Excellgen.com
Richard J Martin
National Jewish Health, 1400 Jackson Street, Denver, Co 80206
Grant 7P01HL036577-23_9003 from National Heart, Lung, And Blood Institute
Abstract: The objectives of the Clinical Core C are 1. To provide a central laboratory for the recruitment and characterization of normal and asthmatic subjects for the clinical components of Projects 1, 2, and 3. 2. To provide a central facility for performance and quality control of pulmonary function testing, antigen skin testing, and methacholine challenge. 3. To provide a central laboratory for collection and analysis of bronchoalveolar lavage fluid and biopsy tissue. 4. To coordinate the distribution of bronchoalveolar lavage cells and fluid, and biopsy tissue to the investigators in Projects 1, 2, and 3. 5. To coordinate the database development of all clinical and laboratory data on normal subjects and patients with asthma as well as transmittal of the data to the individual investigators. 6. To facilitate interproject communication concerning both clinical findings and technical accomplishments. In doing so, the clinical aspects of this Program Project grant will function at a high standard
Keywords: ATGN; Adrenal Cortex Hormones; Allergens; Antigens; Apparatus and Instruments; Asthma; Biopsy; Body Tissues; Bronchial Asthma; Bronchial-Dilating Agents; Bronchioalveolar Lavage; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Bronchodilators; Bronchoscopy with Bronchoalveolar Lavage; Bronchoscopy/Lavage; Cells; Characteristics; Clinical; Collection; Communication; Corticoids; Corticosteroids; Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Development; Douching, other than vaginal; Equipment and Supplies; Human Resources; Hypersensitivity skin testing; Individual; Investigators; Irrigation; Irrigation, other than vaginal; Laboratories; Lavage; Lavage, Bronchopulmonary; Liquid substance; Lung Function Tests; Lung Lavage; Lung Parenchyma; Lung Tissue; Manpower; Morphology; Nonvaginal irrigation; Nonvaginal lavage; P01 Mechanism; P01 Program; Patients; Performance; Procedures; Process; Program Project Grant; Program Research Project Grants; Programs (PT); Programs [Publication Type]; Pulmonary function tests; Quality Control; Recruitment Activity; Research Personnel; Research Program Projects; Researchers; Resistance; Respiratory Function Tests; Respiratory physiology; Skin Tests; Steroid Compound; Steroids; Structure of parenchyma of lung; Therapeutic Corticosteroid; Tissues; Training; airway epithelium infalmmation; airway inflammation; bronchopulmonary lavage therapy; clinical data repository; clinical data warehouse; computerized; data repository; fluid; high standard; hypersensitivity test; immunogen; immunologic skin test; improved; irrigation therapy; lavage therapy; liquid; lumen dilator; lung function; methacholine; personnel; programs; pulmonary function; recruit; relational database; resistant; respiratory function
Project start date: 2009-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2010
7P01HL036577-23_9003 (2009): $379196
INFLAMMATORY CASCADE IN NOCTURNAL ASTHMA
Richard J Martin, Professor And Director
National Jewish Medical And Res Ctr Denver, Co 80206
Grant 5P01HL036577-150008 from National Heart, Lung, And Blood Institute
Abstract: The nocturnal worsening of asthma has a profound effect on patients in regard to daily activities, morbidity and mortality. Investigation into the nocturnal aspect of asthma has enlightened us about the alterations that take place in regard to pathophysiology. Hence, better treatment programs have been developed based upon a chronotherapeutic approach. It appears that a major underlying factor in nocturnal asthma is the inflammatory response which occurs on a circadian basis. The mechanism which initiates this inflammatory cascade is not well understood. This proposal will attempt to establish the sequence of events which occur during the night that trigger the inflammatory response. Our general hypothesis is that in patients with nocturnal asthma, the feedback mechanism to decrease the inflammatory process, i.e., corticotropin releasing hormone and cortisol, is altered and thus leads to the overnight increase in airways inflammation and decrements in lung function. This increase in inflammation includes the production of cytokines IL-2 and IL-4 which cause a reduction in glucocorticoid receptor binding affinity overnight. Thus, we will determine the circadian alterations in CRH in relation to lung function and inflammation. We will then separate the direct effect of CRH by infusion from its effect via increased cortisol output by blockade of adrenal function with metyrapone. Additionally, since we have shown interleukin-1beta(IL-1beta) to be increased at night in bronchoalveolar lavage fluid and IL-1beta is involved in feedback mechanisms of CRH release, its relationship to the inflammatory process will be investigated. Finally, since a reduction in corticosteroid receptor binding affinity occurs with increased inflammation, this aspect will be evaluated in regard to CRH and cortisol control. By establishing the mechanisms which initiate the inflammatory response at night, a better understanding of inflammation in asthma during both day and night will be developed. This will then lead to potentially better therapeutic interventions for all asthma patients.
Keywords: asthma, circadian rhythm, corticotropin releasing factor, hormone regulation /control mechanism, inflammation, respiratory function, sleep, corticosteroid receptor, cortisol, interleukin 1, interleukin 2, interleukin 4, pituitary adrenal axis, receptor binding, clinical research, diagnostic respiratory lavage, human subject, respiratory airflow measurement
Project start date: 2000-07-01
Project end date: 2001-06-30
FOSTERING COLLABORATIONS AND THE CAREER OF A NEWLY RECRUITED PULMONARY SCIENTIST
Richard J Martin
National Jewish Health, 1400 Jackson Street, Denver, Co 80206
Grant 5P30HL101294-02 from National Heart, Lung, And Blood Institute
Abstract: The long-term goal of National Jewish Health (NJH) is to improve the lives of patients with lung disease both through direct patient care, and a synergistic combination of clinical, translational and basic research. The general strategy is to recruit physicians and scientists that focus on lung disease and biology, and to foster strong collaborations. Specifically, last fall, NJH undertook a national search for a physician-scientist with an outstanding research background and an interest in airway biology and disease. As a result of this effort, the Pulmonary Division successfully recruited an outstanding, newly independent physician-scientist to join the faculty and conduct research on glucocorticoid signaling. Dr. Anthony Gerber received his MD/Ph.D. at the University of Washington in 1998, and completed his training at the University of California, San Francisco in 2004. He has recently developed an exciting research program on tissue and promoter specific mechanisms of glucocorticoid signaling. This is an area with significant relevance to airway biology and the goals of NJH. Glucocorticoids are among the most widely used drugs in clinical medicine and are central in the treatment of asthma and other immune-mediated diseases. However, severe side effects and resistance complicate their use in clinical practice. A key issue in glucocorticoid receptor (GR) biology and pulmonary therapeutics is to understand the beneficial and harmful effects of glucocorticoid signaling, in particular cell types within the lung, and to define the molecular mechanisms that control these activities. State-of-the-art multiplexed methods to analyze gene expression will be used to address this research area, methods that are broadly applicable to the study of lung disease. With the funds from the PSO award Dr. Gerber´s research programs on glucocorticoid signaling will be advanced, collaborations on disease modifying pathways in the lung and multiplexed analysis of gene expression will be facilitated. This will be accomplished by (1) investments in infrastructure for Dr. Gerber´s lab and employing skilled personnel to assist with his investigations, (2) integrating tools and methods for multiplexed gene expression analysis into the investigations of other researchers in the division/core, and (3) forming a committee to oversee Dr. Gerber´s progress. NJH is at the forefront of the treatment and research of lung and immune-mediated diseases, which afflict millions of Americans. This project will advance the understanding of glucocorticoid signaling, which is central in the treatment of many diseases. It will also foster collaborations among a group of outstanding scientists focused on lung disease
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-OD-09-005
5P30HL101294-02 (2010): $719439
1P30HL101294-01 (2009): $633498
ASTHMA CHRONOBIOLOGY: CENTRAL AND LUNG INTERACTIONS
Richard J Martin, Department Of Medicine
National Jewish Medical & Res Ctr
denver, Co 80206
Grant 5R01HL064804-03 from National Heart, Lung, And Blood Institute IRG: ZHL1
Abstract: The long term objective of this project is to understand the chronobiology of asthma so as to improve asthma treatment in general thereby decreasing asthma morbidity and mortality. The nocturnal worsening of asthma is associated with the three major asthma characteristics reversible airway obstruction, bronchial hyperresponsiveness, and inflammation. These characteristics occur on a circadian (24 hour) basis and thus must be controlled by other endogenous circadian events. The specific aims will evaluate how these factors are controlled as well as why the nocturnal asthma patient does not readily awake so as to treat decreases in lung function as would occur more readily during the daytime hours. To these ends, the specific aims will determine (1) if clock gene(s) expression in blood and lungs exhibit a circadian pattern and its relationship to certain other outcome factors as lung function, melatonin, and inflammatory markers; (2) if melatonin produces a state of enhanced inflammation that results in decreased steroid sensitivity; (3) if there is a dysregulation of corticotropin releasing hormone production in response to enhanced inflammation at night; and (4) the effects of melatonin on physiologic and arousal responses during sleep
Keywords: asthma, bioperiodicity, gene expression, lung, melatonin, neuroendocrine system, sleep arousal, bronchospasm, corticosteroid receptor, corticotropin releasing factor, cytokine, hormone sensitivity /resistance, inflammation, monocyte, pharmacokinetics, respiratory epithelium, respiratory function, steroid, tumor necrosis factor alpha adult human (21+), clinical research, human subject
Project start date: 2000-04-01
Project end date: 2004-03-31
5R01HL064804-03 (2002): $346050
Sponsored Links Excellgen http://Excellgen.com
5R01HL064804-02 (2001): $346050
1R01HL064804-01 (2000): $304140
5R01HL064804-04 (2003): $346050
MATURATION OF AIRWAY RELAXANT RESPONSES
Richard J Martin, Professor And Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5R01HL056470-09 from National Heart, Lung, And Blood Institute IRG: ZRG1
Abstract: Preterm infants exposed to supplemental oxygen are predisposed to the development of bronchopulmonary dysplasia [BPD] which is associated with increased airway resistance and subsequent airway hyperreactivity. The current proposal is to extend our earlier studies on regulation of airways by characterizing maturation of airway relaxant responses during normal development and in response to hyperoxic exposure. We will initially test the hypothesis that there is upregulation of airway smooth muscle relaxant mechanisms during early postnatal life, secondary to increased production of nitric oxide and relaxant prostaglandins [PGE2 and PGI2] from airway epithelium. Our preliminary data demonstrate that administration of substance P [SP] and cholinergic stimulation elicit a relaxant response of preconstricted tracheal smooth muscle which declines with postnatal maturation, is mediated by release of endogenous NO and PGE2, and is impaired after hyperoxic exposure. We will therefore additionally test the hypothesis that hyperoxic stress impairs NO and PGE2-mediated airway smooth muscle relaxation secondary to impaired NO and PG-mediated signaling pathways in airway smooth muscle. Physiologic relaxant responses of preconstricted airways will be characterized in maturing rat pups under normoxic and hyperoxic conditions. These findings will be correlated with expression and activity of nitric oxide synthase (NOS) and cyclooxygenase (COX) isoforms in airway epithelium. In airway smooth muscle we will determine developmental and hyperoxia-induced changes in prostaglandin (PGE2) receptor subtypes, Gi protein expression and cAMP production. Maturational and hyperoxia-induced effects on NO/cGMP signaling pathways including expression and activation of cGMP dependent protein kinase (PKG) will be assayed. Physiologic responses will then be correlated with levels of free intracellular Ca2++ and myosin light chain dephosphorylation in airway smooth muscle in normoxic and hyperoxic tissues. Characterization of the mechanisms underlying deficient airway smooth muscle relaxation will help to elucidate the pathologic mechanisms underlying airway hyperreactivity secondary to hyperoxia-induced lung injury, as in preterm infants who develop bronchopulmonary dysplasia. This should lead to the design of new therapeutic approaches for such disorders.
Keywords: bronchomotion, growth /development, hyperoxia, respiratory muscle, bronchopulmonary dysplasia, cGMP dependent protein kinase, cyclic AMP, cyclic GMP, guanine nucleotide binding protein, muscle metabolism, muscle relaxation, myosin light chain kinase, nitric oxide, nitric oxide synthase, pathologic process, prostaglandin E, prostaglandin receptor, receptor binding, respiratory airway pressure, respiratory epithelium, substance P, laboratory rat, newborn animal, tissue /cell culture, western blotting
Project start date: 1996-05-03
Project end date: 2006-12-31
5R01HL056470-09 (2005): $403354
5R01HL056470-08 (2004): $391605
5R01HL056470-07 (2003): $380200
5R01HL056470-06 (2002): $369126
2R01HL056470-05A1 (2001): $358380
Airway-Central Nervous System Control
Richard J Martin, Professor And Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5R01HL050527-12 from National Heart, Lung, And Blood Institute IRG: RESP
Abstract: Chronic airway diseases such as bronchial asthma and chronic obstructive bronchitis share the salient features of inflammation, hyperresponsiveness to various inhalants, and airway narrowing. Although these two conditions result in enormous morbidity and social cost, the central nervous system mechanisms involved in airway hyperreactivity remain poorly understood. In the prior funding cycle of this proposal we have characterized the primary neurochemical(s) and receptor subtypes involved in transmission of excitatory inputs from the respiratory tract to the nucleus tractus solitarius (NTS) neurons; from these second order sensory cells to airway-related vagal preganglionic motor neurons (AVPNs); and from AVPNs back down to the airways. As a natural continuation of this work, we now focus on inhibitory pathways that regulate cholinergic drive to the airways. Neuroanatomical studies will define the normal neural circuitry between inhibitory GABAergic, catecholaminergic, or serotonergic cell groups and AVPNs. In these studies, retrograde tracing will be used to define AVPNs projecting to the trachea. Dual or triple labeling immunocytochemistry will be used to simultaneously locate neurotransmitters, their receptors, and AVPNs. Tissues will be examined using light microscopy, confocal microscopy, and electron microscopy. Protein levels will be measured by Western blotting. In physiological studies, we will microinject uptake inhibitors, specific agonists, or antagonists into the rostral nucleus ambiguus (rNA, where AVPNs are abundant), to define the functional roles of specific inhibitory neurotransmitters and their receptors on basal and reflex-induced changes in tracheal tone and airway resistance. Subsequently, we will test the hypothesis that repeated exposure to allergens in sensitized animals induces morphological and physiological changes in central inhibitory influences, resulting in a shift from inhibitory to excitatory transmission. These changes lead to a hyperexcitable state of AVPNs and to airway hyperreactivity. The results of these studies will provide necessary knowledge in the neural control of the airways and will support the development of novel pharmaceutical strategies which target the central nervous system for the treatment of airway disorders.
Keywords: acetylcholine, central nervous system, gamma aminobutyrate, neuroregulation, neurotransmitter transport, preganglionic fiber, respiratory hypersensitivity, serotonin, GABA receptor, allergen, desipramine, fluoxetine, neural transmission, neuroanatomy, neurochemistry, receptor expression, serotonin receptor, solitary tract nucleus, confocal scanning microscopy, electron microscopy, ferret, horseradish peroxidase, immunocytochemistry, light microscopy, stereotaxic technique, western blotting
Project start date: 1995-01-01
Project end date: 2009-03-31
5R01HL050527-12 (2007): $329612
Modulation And Resistance Of Levamisole Receptor Channels
Richard J Martin, Professor And Chair
Iowa State University 1138 Pearson Hall Ames, Ia 500112207
Grant 5R01AI047194-07 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: Ascariasis and hookworm infection affect 1.6 billion people across the world. Anthelmintics, including levamisole and related drugs (pyrantel), are used to combat nematode parasites, and resistance is a threat. Our long-range objective is to improve human health by increasing the efficacy of anthelmintic drugs by identifying approaches to reverse resistance. The objective of this application is to test single-channel properties of levamisole receptors and a model that describes changes in the sensitivity of nematodes to levamisole and alters potency. Our central hypothesis is that the structure and pore of the L-subtype acetylcholine receptor ion-channel on nematode muscle makes it more sensitive to levamisole and more permeable to Ca; and the increased response of acetylcholine channels (modulation) produced by the neuropeptide, AF2, involves cAMP, Ca entry and kinase activity. The rationale for the research is that, as the mechanisms for modulating responses to levamisole activated receptor channels become known, pharmacological approaches can be formulated to overcome resistance. We will use muscle preparations of A. suum, C. elegans and null-mutants with current-clamp, voltage-clamp and patch-clamp technology to test the Ca permeability and subunit composition of L-subtype acetylcholine channels and to test a model for AF2 modulation. We will pursue 3 aims 1) determine the Ca permeability of N-, L- and B- subtypes of A. suum muscle acetylcholine receptors and thereby identify a preferred target site; 2) determine in patch-clamp experiments in C. elegans, the subunit requirements of the L-subtype acetylcholine channel; 3) characterize, n A. suum muscle, the mechanism and pharmacology by which calcium and AF2 affect the opening of different AChR channel subtypes, in order to increase responses and potency of cholinergic anthelmintics. The research is innovative because we are combining new knowledge from C. elegans with advanced electrophysiology of nematode parasites including muscle-vesicle preparations for patch-clamp recordings. We expect the research to identify additional strategies that increase the potency of cholinergic anthelmintics. The research is significant because application of the results will to lead to new approaches to control and overcome resistance to anthelmintics of the levamisole class.
Keywords: levamisole, receptor, Ascaris, Caenorhabditis elegans, Nematoda, acetylcholine, anthelmintic, calcium, calcium channel, cell biology, diarrhea, electrical potential, electrophysiology, element, emotion, environment, hand, health, helminthiasis, human, infection, ion, lead, method development, model, muscle, mutant, neuropeptide, neuroscience, nicotine, parasitic gastrointestinal disorder, pharmacology, phosphorylation, publication, university, voltage /patch clamp
Project start date: 2000-03-01
Project end date: 2010-12-31
5R01AI047194-07 (2007): $281927
Sponsored Links Excellgen http://Excellgen.com