LUNG GENOMICS RESEARCH CONSORTIUM
E Avrum
University Of Colorado Denvercity: Aurora country: United States (us)
Grant 7RC2HL101715-03 from National Heart, Lung, And Blood Institute
Abstract: Chronic lung diseases represent a broad spectrum of chronic fibrosing/inflammatory lung conditions that are for the most part poorly responsive to treatment and often fatal. COPD/emphysema is the fourth leading cause of death in the United States and the incidence and rate of death from pulmonary fibrosis is increasing each year. Although progress has been made in interpretation of the clinical, radiological, and pathological features of chronic lung disorders, and progress in determining the pathobiology continues, the causes, biologic mechanisms, and therapeutic options remain obscure. Moreover, predicting individuals or populations at risk for developing any of these complex diseases, at present, is not possible. To address this challenge, we plan to create a genetic, molecular, and quantitative clinical phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. The composite genetic, genomic, and epigenetic signature combined with quantitative clinical phenotypes has the potential to characterize the dynamic biological state of a complex disease and complement existing diagnostic approaches that are reliant on traditional clinical measures of disease. In the proposed project, we plan to extend the scope and impact of the NHLBI Lung Tissue Research Consortium (LTRC) biorepository by creating the Lung Genomics Research Consortium (LGRC), a comprehensive genetic, molecular, and quantitative clinical phenotyping warehouse. Our overall hypothesis is that a genetic, molecular, and quantitative clinical phenotyping warehouse combined with a rich clinical database will enable the lung research community to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. We plan to pursue this hypothesis through the following aims. Specific Aim 1 Establish a genetic, genomic, and epigenetic molecular library to complement the existing clinical database in the LTRC. Specific Aim 2 Develop a quantitative clinical phenotyping platform using existing LTRC data, as well as an enhanced data set including novel quantitative CT and histology imaging analyses. Specific Aim 3 Establish a publicly-accessible database that would integrate the genetic, molecular, and quantitative phenotyping data with the existing clinical data in the LTRC and provide query and data exploration tools that are easily accessible to the lung research community. These discoveries will enable clinicians to 1) identify individuals at risk of developing chronic lung diseases; 2) diagnose these conditions earlier; 3) identify novel mechanisms that cause these diseases; 4) reclassify disease entities into categories more representative of molecular and cellular pathogenic mechanisms regardless of traditional disease categories; and 5) develop personalized approaches to treatment. Chronic lung diseases affect a significant portion of the population, the incidence of COPD/emphysema and idiopathic interstitial pneumonia are increasing annually, and COPD is the fourth leading cause of death in the U.S. (www.cdc.gov). Despite major investments that have been made in lung research over the past two decades, these disease remains major public health problems that paradoxically are increasing in prevalence, incidence, and severity. To address this challenge, we plan to create a genetic, molecular, and quantitative phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. These discoveries will enable clinicians to 1) identify individuals at risk of developing chronic lung diseases; 2) diagnose these conditions at an earlier stage; 3) identify novel mechanisms that cause chronic lung disease; and 4) eventually develop personalized therapeutic strategies for intervention
Relevance: Chronic lung diseases affect a significant portion of the population, the incidence of COPD/emphysema and idiopathic interstitial pneumonia are increasing annually, and COPD is the fourth leading cause of death in the U.S. (www.cdc.gov). Despite major investments that have been made in lung research over the past two decades, these disease remains major public health problems that paradoxically are increasing in prevalence, incidence, and severity. To address this challenge, we plan to create a genetic, molecular, and quantitative phenotyping data warehouse with bioinformatic tools that will empower investigators to make fundamental discoveries in disease pathogenesis, refine diagnostic criteria, and lead to real gains in personalized medicine. These discoveries will enable clinicians to: 1) identify individuals at risk of developing chronic lung diseases; 2) diagnose these conditions at an earlier stage; 3) identify novel mechanisms that cause chronic lung disease; and 4) eventually develop personalized therapeutic strategies for intervention
Project start date: 2009-09-30
Project end date: 2012-08-31
Budget start date: 15-AUG-2011
Budget end date: 31-AUG-2012
7RC2HL101715-03 (2010): $1654805
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to E Avrum
AIRWAY GENE EXPRESSION IN SMOKERS: AN EARLY DIAGNOSTIC BIOMARKER FOR LUNG CANCER
E Avrum, Associate Professor
Boston University Medical Campuscity: Boston country: United States (us)
Grant 5R01CA124640-05 from National Cancer Institute
Abstract: Lung cancer is the leading cause of cancer death in both men and women in the United States. The high mortality in patients with lung cancer results, in part, from the lack of effective tools to diagnose the disease at an early stage before it has spread to regional nodes or has metastasized beyond the lung. Our long-term goal is to develop a relatively noninvasive means of assessing the degree of airway epithelial cell damage and the risk for having or developing lung cancer among smokers. The objective of this application is to develop an intrathoracic (mainstem bronchus) airway gene expression profile capable of serving as an early diagnostic biomarker for lung cancer in smokers with clinical suspicion of disease. This approach is based on the hypothesis that patterns of gene expression in the histologically normal airway epithelium of a smoker reflect the types and degree of damage induced by the tobacco smoke and can predict that smoker´s risk for having lung cancer. Using oligonucleotide microarrays, we have identified a gene expression signature in histologically normal large airway epithelial cells obtained at bronchoscopy that can serve as a highly sensitive and specific biomarker for distinguishing smokers with and without lung cancer. In this proposal, we will 1) validate this diagnostic airway biomarker in a large independent cohort of smokers with suspicion for lung cancer; 2) evaluate our biomarker´s accuracy in predicting the presence of lung cancer in stage 1 disease; 3) integrate airway gene expression profiles with established clinical risk factors for disease to produce a clinicogenomic predictive model that can guide patient evaluation and management; 4) develop a second gene expression signature in normal airway epithelium capable of distinguishing small cell vs. non-small cell lung cancer using novel reverse engineering algorithms. These studies will produce a relatively noninvasive tool effective in diagnosing lung cancer at an early and potentially curable stage. These gene expression-based biomarkers may eliminate the need for additional and often more invasive diagnostic tests that are costly, incur risk, and prolong the diagnostic evaluation of smokers with suspicion of lung cancer
Keywords: Age; airway epithelium; Algorithms; base; biomarker; Biopsy; Bronchi; Bronchoscopy; Cancer Etiology; cell injury; cell type; Cells; Cessation of life; cigarette smoking; Clinical; Clinical Data; clinically relevant; cohort; Collaborations; Computational algorithm; computerized tools; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; disease diagnosis; disorder subtype; Drug Metabolic Detoxication; Early Diagnosis; Effectiveness; Engineering; Enzymes; Epigenetic Process; Epithelial; Epithelial Cells; Evaluation; Excision; experience; Gene Expression; Gene Expression Profile; Genetic; Goals; Histologic; innovation; Interdisciplinary Study; Ireland; Lung; lung carcinogenesis; Malignant neoplasm of lung; Malignant Neoplasms; Medical center; men; minimally invasive; Modeling; Molecular Profiling; Mortality Vital Statistics; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Non-smoker; novel; Oligonucleotide Microarrays; Operative Surgical Procedures; Outcome; Patients; Pattern; Play; Population; predictive modeling; Predictive Value; Probability; programs; Pulmonary Mass; Recruitment Activity; research clinical testing; Research Personnel; response; Risk; Risk Factors; Role; Sampling; Screening procedure; Smoker; Smoking History; Staging; Testing; Therapeutic; Tobacco; Tobacco smoke; tool; Toxin; United States; Voting; Weight; Woman; Work
Project start date: 2007-05-01
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5R01CA124640-05 (2011): $277875
LINKING AIRWAY GENOMICS TO THE PATHOGENESIS AND CLINICAL HETEROGENEITY OF COPD
E Avrum, Associate Professor
Boston University Medical Campuscity: Boston country: United States (us)
Grant 5R01HL095388-04 from National Heart, Lung, And Blood Institute
Abstract: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and its mortality rate is expected to climb steadily over the next 20 years. In the US, this condition causes over 700,000 hospitalizations per year and leads to $20-26 billion in annual health care expenditures. There is currently no cure for COPD, and the limited therapies currently available mainly reduce symptoms rather than reverse the disease or prevent its progression. While the role cigarette smoke plays in COPD is undisputed, the mechanism by which inhaled smoke contributes to disease pathogenesis remains unclear. One of the major barriers to the development of new approaches to diagnose and manage COPD is the clinical heterogeneity displayed by COPD patients. While COPD has been defined as a disease state characterized by airflow limitation that is not fully reversible, there are diverse clinical, radiographic, and pathologic findings that likely reflect different underlying molecular and pathogenic disease mechanisms. Cigarette smoke causes an airway-wide "field of injury", and gene expression in bronchial airway cells of smokers obtained by brushings at bronchoscopy reflects both this injury and subsequent disease-specific processes. This proposal examines the hypothesis that determining the gene-expression profile of airway epithelial cells in individuals with and without COPD will provide insights into the molecular pathogenesis of COPD and specific COPD-related traits, including degree of airflow obstruction, emphysema, small airways disease, and the rate of disease progression. Alterations in airway gene and microRNA expression will be used to define the underlying pathways that are perturbed by COPD, and to define novel molecular subclasses of COPD that may contribute to the clinical diversity of the disease. Patterns of airway gene expression will be linked to longitudinal decline in lung function, providing a way to identify individuals at risk for rapid disease progression and an understanding of the mechanisms responsible for variations in their rate of functional decline. How the expression of COPD-related airway gene-expression profiles change during disease progression within lung tissue will elucidate dynamic disease-related processes. The reversibility of these gene expression changes upon treatment with various existing and novel COPD drugs will determine whether airway gene expression signatures can serve as an intermediate marker for evaluating COPD treatments. Finally, the identification of heritable genetic variants that influence the underlying pathways that are responsible for COPD-specific gene expression changes, and testing their ability to identify individuals at risk for COPD, will result in genetic markers of disease susceptibility and progression. The proposed work applies powerful whole-genome exon level and microRNA expression platforms and a variety of novel computational methodologies to samples from a series of large, unique, and well-characterized existing cohorts, and will result in an unprecedented and detailed view of the molecular processes that contribute to COPD pathogenesis. (End of )
Keywords: ing; Affect; Aftercare; airway epithelium; Alternative Splicing; alveolar destruction; Area; base; Bioinformatics; Biological Assay; Biometry; Boston; Breathing; British Columbia; bronchial epithelium; Bronchoscopy; Cause of Death; Cells; Chest; Chronic Obstructive Airway Disease; cigarette smoke; cigarette smoking; Clinical; cohort; Collaborations; Collection; Complex; Computing Methodologies; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Disease susceptibility; disorder subtype; Epithelial; Epithelial Cells; Evaluation; Exhibits; Exons; Framingham Heart Study; functional decline; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Determinism; Genetic Markers; genetic variant; Genome; genome-wide; Genomics; Genotype; Health; Health Expenditures; Heterogeneity; Hospitalization; Image; Immune response; Individual; Injury; innovation; insight; Interdisciplinary Study; Link; Lung; Lung Transplantation; Measurement; Measures; member; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mortality Vital Statistics; Natural History; novel; novel strategies; Obstruction; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Play; prevent; Process; public health medicine (field); Pulmonary Emphysema; pulmonary function; pulmonary function decline; Pulmonary Function Test/Forced Expiratory Volume 1; Research; Research Personnel; Resected; Resources; Respiratory physiology; Risk; RNA; RNA analysis; Role; Sampling; Series; Severities; small airways disease; Smoke; Smoker; Smoking; SNP genotyping; Specimen; Structure of parenchyma of lung; Surface; Symptoms; Testing; Therapeutic; Thick; Tissue Sample; Tissues; tool; trait; United States; Universities; Variant; Work; X-Ray Computed Tomography
Relevance: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and a significant public health burden. There is currently no cure for COPD, and the limited available therapies are mainly used to reduce symptoms. The purpose of this study is to develop an understanding of the processes that contribute to COPD pathogenesis, ultimately yielding tools for stratifying and treating COPD patients based on the molecular processes that are responsible for their disease
Project start date: 2008-09-24
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-HL-08-006
5R01HL095388-04 (2011): $692695