R01HL155742

OMIC Determinants of Longitudinal Lung Function in Asthma - Project Summary

Further Characterization of Longitudinal Lung Function (LLF) throughout adulthood in asthmatics is critically important, as low lung function correlates with increased exacerbations, morbidity, and mortality. Precise genomic and metabolomic profiling of the biological mechanisms underlying LLF trajectories will be instrumental in understanding and ameliorating lung function deterioration.

MicroRNAs (miRs; short non-coding RNAs) exhibit broad impact on inflammatory cascades, leading to airway remodeling and chronic airway obstruction, and specific metabolites provide a measure of real-time inflammatory changes that reflect both genetic and environmental influences. Therefore, the combined use of miRs and metabolites has great potential to provide critical insight into disease physiology and identify mechanisms to regulate, diagnose, and prognosticate LLF.

The objective of this proposal is to identify miRNA and metabolomic determinants of LLF patterns, classified using longitudinal spirometry measures from electronic medical records (EMRs), that accurately identify individuals with asthma at the greatest risk of progression to more serious chronic lung obstruction. Our central hypothesis is that LLF trajectories are regulated by specific sets of genes, miRNAs, and metabolites that can 1) inform on underlying biological dysregulation and 2) serve as biomarkers to distinguish clinically actionable patterns of LLF, enabling personalized medicine approaches through the identification of multiomic therapeutic targets.

We will explore this hypothesis by generating the novel and unique Biobank of Asthmatics with Longitudinal Lung Function (BALLF) cohort, which includes rigorous LLF phenotyping generated from electronic medical records (Aim 1A) and global metabolomics profiling and miRNA sequencing (Aim 1B) supplementing existing genetic and phenotypic data. We will identify metabolites (Aim 2A) and miRNAs (Aim 2B) associated with these LLF, capitalizing on our rich preliminary data implicating sphingolipid and eicosanoid biosynthesis to guide our analyses. Finally, we will leverage our extensive systems biology expertise to integrate this multiomic data to improve our biological understanding of LLF (Aim 3A) and to develop clinically translatable biomarkers (Aim 3B).

Crucially, we have the ability to both validate these findings and to assess their generalizability in two existing independent cohorts of asthmatics. This will represent the first integrative omic study of LLF trajectories in asthma focusing on the unique combination of miRs, metabolites, and genes. As such, the findings of this innovative proposal have tremendous potential to elucidate the biological mechanisms of lung function decline and to influence the management of asthmatics at risk of this devastating complication.

Brigham & Womens Hospital

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 408% from $771,762 to $3,917,165.