A Developmental Basis for Chronic Obstructive Lung Disease

描述（由申请人提供）：申请人描述了一个为期5年的职业发展计划，作为一名生物数学家，在生物医学信息学和呼吸病理生物学的领导者Isaac Kohane和Scott Weiss的指导下，在基础呼吸研究方面进行独立的学术研究。该计划的两个目标是(1)获得基本的生物学知识和技能，成为一名独立的肺发育和病理生物学研究人员-职业发展一半；(2)发展一个全面的肺发育分子功能分类学，作为表征慢性阻塞性肺疾病（COPD）组成表型的发育基础的框架-研究一半。候选人将充分利用波士顿儿童医院和钱宁实验室丰富的多学科资源，促进学术发展。研究：我们研究了肺个体发生中的分子发育里程碑与慢性阻塞性肺疾病（COPD）分子病理之间的关系，以了解COPD表型异质性的分子发育基础。我们的前提建立在申请人使用小鼠发育模型研究人类恶性肿瘤的成功先前工作的基础上。我们的中心假设是，描述COPD疾病进展的分子事件反映了胚胎肺发育程序，但是一个功能失调的程序，而不是一个有序的程序。我们通过3个具体目标来解决这一假设：(1)定义哺乳动物肺发育的分子分类，(2)将每个肺发育阶段的分子特征从(1)映射到本体/功能属性，以及(3)确定（1-2）中定义的COPD每个组成表型固有的发育相关性，这些相关性将用于创建COPD表型的预后模型。我们的方法将使用整合基因组学作为一个实用的支架来合成大型多因子数据集。相关性：如果成功，我们的方法可以为COPD表型提供一种新的分子特征（基于发育或其他）。这样的定义可能会导致我们目前基于临床表型固有的不精确性的COPD定义的急需的改进。这样的定义在COPD的描述性和介入性研究中都有价值。（摘要结束）

DESCRIPTION (provided by applicant): 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. 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. (End of Abstract)