Sunita Sharma, Ph.D. - US grants

DESCRIPTION (provided by applicant): Chronic obstructive respiratory diseases, including both chronic obstructive pulmonary disease (COPD) and asthma, are among the leading causes of morbidity and mortality worldwide. Pulmonary function is an independent predictor of survival, as well as a specific marker of disease severity in asthma and COPD. Measures of pulmonary function track along similar percentile curves from shortly after birth into adulthood, suggesting that the genetic programming of lung development and in utero exposures are critical determinants of lung function later in life. The development of novel therapies requires a comprehensive catalog of modifiable genetic targets and the molecular pathways that contribute to the development and progression of impaired lung function in susceptible populations. Genomic technologies including expression microarrays and high-throughput genotyping platforms offer an unprecedented opportunity to advance this process. "Integrative genomics" seeks to combine genotype data with gene expression data to more rapidly identify loci contributing to the function of a gene. The overarching premise of this project is to train the primary investigator to combine gene expression with genotypic data of early human lung development to identify critical developmental regulatory variants and the biologic pathways that contribute to the development and progression of impaired lung function in asthma and COPD. We have outlined a series of courses that will allow the primary investigator to apply an integrative genomic approach to human fetal lung development. Success in this project will foster the primary investigator's transition to independent research in respiratory genomics. Furthermore, results of this project could lead to the development of novel therapies for patients with obstructive respiratory diseases. PUBLIC HEALTH RELEVANCE: Chronic obstructive respiratory diseases, including both asthma and chronic obstructive pulmonary disease (COPD), are among the leading causes of morbidity and mortality, resulting in over $45 billion in annual healthcare costs in the US alone. A better understanding of the biologic pathways that influence lung function impairment may identify innovative therapeutic targets for patients with obstructive airways diseases. Novel therapies have the potential to substantially decrease the morbidity, mortality, and the financial burden related to these diseases.

? DESCRIPTION (provided by applicant): Asthma is a major public health problem affecting over 23 million people in the US, resulting in excess of $50 billion in healthcare expenditures per year. There is increasing evidence suggesting that in utero exposures can influence the genome resulting in increased susceptibility to asthma. In utero smoke (IUS) exposure has been associated with asthma susceptibility; however, the biologic mechanisms underlying this association have not been fully elucidated. MicroRNAs (miRNAs) are known to fine-tune the relative expression of hundreds of target genes and provide stability to gene expression regulatory networks. Animal models demonstrate that miRNAs are integral to normal in utero development, and that abnormal miRNA expression during development results in postnatal disease, suggesting that miRNAs that are modified during development by IUS exposure may be critical determinants of asthma susceptibility later in life. However, the role of miRNAs has neither been investigated in the context of IUS exposure in human lung development, nor in the developmental origin of asthma. We propose a novel integrative genomics approach incorporating miRNAs, gene expression, and DNA methylation in human subjects to investigate the role of miRNAs and their integrative networks (INs) in lung development and asthma susceptibility. Our proposal describes our plan to: identify miRNAs and the INs that are expressed, and modified by IUS exposure in developing human lung, and are also associated with asthma susceptibility and disease severity. In addition to vastly expanding our knowledge of the role miRNAs and their INs in human lung development and the signature of IUS exposure, this project will aid in the identification of pathways for novel therapeutic agents for the treatment of asthma.