The applicant describes a 5-year career development program leading to independent academic research in basic respiratory research as a biological mathematician under co-mentors Isaac Kohane and Scott Weiss, leaders in biomedical informatics and respiratory pathobiology respectively. The 2 goals of this program are (1) to gain the foundational biological knowledge and skills to become an independent researcher in lung development and pathobiology - for the career development half, and (2) to develop a comprehensive molecular-functional taxonomy of lung development as a framework for characterizing the developmental basis of constituent phenotypes of chronic obstructive pulmonary disease (COPD) - in the research half. The candidate will have full access to the rich multi-disciplinary resources at Children's Hospital Boston and the Channing Laboratory for academic growth. RESEARCH: We address the association between molecular developmental milestones in lung ontogeny and the molecular pathology of chronic obstructive pulmonary disease (COPD) in an effort to understand the molecular-developmental basis underlying COPD phenotypic heterogeneity. Our premise builds on successful prior work of the applicant in using mouse developmental models to investigate human malignancies. Our central hypothesis is that the molecular events that describe disease progression in COPD reflect embryonic lung development programs but in a dysfunctional rather than an ordered program. We resolve this hypothesis via 3 specific aims which: (1) Define the molecular taxonomy of mammalian lung development, that (2) Maps the molecular hallmarks for each lung development phase from (1) to ontologic / functional attributes, and (3) Identify the developmental correlates - defined in (1-2) - inherent to each constituent phenotype of COPD that will be used to create a prognostic model for COPD phenotypes. Our approach will use integrative genomics as a practical scaffold to synthesize large multi-factorial datasets.

Public Health Relevance

If successful, our approach could provide a novel molecular signature (developmentally-based or otherwise) for COPD phenotypes. Such a definition could lead to a much needed refinement of our current definitions of COPD, which are based on the inherent imprecision of clinical phenotyping. Such definitions could prove of value in both descriptive and interventional studies in COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25HL091124-05
Application #
8307848
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Tigno, Xenia
Project Start
2008-08-01
Project End
2013-10-31
Budget Start
2012-08-01
Budget End
2013-10-31
Support Year
5
Fiscal Year
2012
Total Cost
$148,500
Indirect Cost
$11,000
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Kho, Alvin T; Sharma, Sunita; Davis, Joshua S et al. (2016) Circulating MicroRNAs: Association with Lung Function in Asthma. PLoS One 11:e0157998
Haas, David M; Lai, Dongbing; Sharma, Sunita et al. (2016) Steroid Pathway Genes and Neonatal Respiratory Distress After Betamethasone Use in Anticipated Preterm Birth. Reprod Sci 23:680-6
Oh, Djin-Ye; Dowling, David J; Ahmed, Saima et al. (2016) Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures. Mol Cell Proteomics 15:1877-94
McGeachie, Michael J; Yates, Katherine P; Zhou, Xiaobo et al. (2016) Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med 374:1842-52
Kho, Alvin T; Chhabra, Divya; Sharma, Sunita et al. (2016) Age, Sexual Dimorphism, and Disease Associations in the Developing Human Fetal Lung Transcriptome. Am J Respir Cell Mol Biol 54:814-21
Beauchemin, Kyle J; Wells, Julie M; Kho, Alvin T et al. (2016) Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development. PeerJ 4:e2318
Sharma, Sunita; Kho, Alvin T; Chhabra, Divya et al. (2015) Glucocorticoid genes and the developmental origins of asthma susceptibility and treatment response. Am J Respir Cell Mol Biol 52:543-53
Park, Jin-Ah; Kim, Jae Hun; Bi, Dapeng et al. (2015) Unjamming and cell shape in the asthmatic airway√ā¬†epithelium. Nat Mater 14:1040-8
Sharma, Sunita; Chhabra, Divya; Kho, Alvin T et al. (2014) The genomic origins of asthma. Thorax 69:481-7
Chhabra, Divya; Sharma, Sunita; Kho, Alvin T et al. (2014) Fetal lung and placental methylation is associated with in utero nicotine exposure. Epigenetics 9:1473-84

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