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.
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.
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