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 #
5K25HL091124-02
Application #
7663868
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Rothgeb, Ann E
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
2
Fiscal Year
2009
Total Cost
$148,500
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Kho, Alvin T; McGeachie, Michael J; Moore, Kip G et al. (2018) Circulating microRNAs and prediction of asthma exacerbation in childhood asthma. Respir Res 19:128
McGeachie, Michael J; Yates, Katherine P; Zhou, Xiaobo et al. (2016) Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma. Am J Respir Crit Care Med 194:1465-1474
McGeachie, M J; Yates, K P; Zhou, X et al. (2016) Patterns of Growth and Decline in Lung Function in Persistent Childhood Asthma. N Engl J Med 374:1842-1852
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
Zhang, Hui; Kho, Alvin T; Wu, Qing et al. (2016) CRISPLD2 (LGL1) inhibits proinflammatory mediators in human fetal, adult, and COPD lung fibroblasts and epithelial cells. Physiol Rep 4:
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
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
Kho, Alvin T; Sharma, Sunita; Davis, Joshua S et al. (2016) Circulating MicroRNAs: Association with Lung Function in Asthma. PLoS One 11:e0157998
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
Park, Jin-Ah; Kim, Jae Hun; Bi, Dapeng et al. (2015) Unjamming and cell shape in the asthmatic airway epithelium. Nat Mater 14:1040-8

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