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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL096833-03
Application #
8268430
Study Section
Special Emphasis Panel (ZHL1-CSR-U (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-07-15
Project End
2014-05-31
Budget Start
2012-06-15
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$136,638
Indirect Cost
$9,825
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Sharma, Sunita; Chhabra, Divya; Kho, Alvin T et al. (2014) The genomic origins of asthma. Thorax 69:481-7
Sharma, Sunita; Litonjua, Augusto (2014) Asthma, allergy, and responses to methyl donor supplements and nutrients. J Allergy Clin Immunol 133:1246-54
Sharma, Sunita; Zhou, Xiaobo; Thibault, Derek M et al. (2014) A genome-wide survey of CD4(+) lymphocyte regulatory genetic variants identifies novel asthma genes. J Allergy Clin Immunol 134:1153-62
Vyhlidal, Carrie A; Riffel, Amanda K; Haley, Kathleen J et al. (2013) Cotinine in human placenta predicts induction of gene expression in fetal tissues. Drug Metab Dispos 41:305-11
Sharma, Sunita; Poon, Audrey; Himes, Blanca E et al. (2012) Association of variants in innate immune genes with asthma and eczema. Pediatr Allergy Immunol 23:315-23
Sordillo, Joanne E; Sharma, Sunita; Poon, Audrey et al. (2011) Effects of endotoxin exposure on childhood asthma risk are modified by a genetic polymorphism in ACAA1. BMC Med Genet 12:158
Sharma, Sunita; Murphy, Amy; Howrylak, Judie et al. (2011) The impact of self-identified race on epidemiologic studies of gene expression. Genet Epidemiol 35:93-101