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，导致在基础呼吸研究中的独立学术研究，作为生物数学家，共同导师Isaac Kohane和Scott韦斯分别是生物医学信息学和呼吸病理学的领导者。该计划的两个目标是（1）获得基础生物学知识和技能，成为肺发育和病理生物学的独立研究人员-职业发展一半，和（2）开发肺发育的全面分子功能分类学作为表征慢性阻塞性肺疾病（COPD）组成表型的发展基础的框架-在研究一半。候选人将有机会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，以促进学术发展。研究：我们探讨了肺个体发育中的分子发育里程碑与慢性阻塞性肺疾病（COPD）的分子病理学之间的关系，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在使用小鼠发育模型研究人类恶性肿瘤方面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，但在一个功能障碍，而不是有序的程序。我们通过3个具体目标来解决这个假设：（1）定义哺乳动物肺发育的分子分类学，即（2）将每个肺发育阶段的分子标志从（1）映射到本体/功能属性，和（3）确定（1 - 2）中定义的发展相关因素-这是COPD的每个组成表型所固有的，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对COPD的定义进行急需的细化，这些定义是基于临床表型的固有不精确性。这些定义在COPD的描述性研究和干预性研究中都有价值。 (End摘要）

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)