Wnt-mediated epithelial-endothelial crosstalk in the generation and regeneration of the lung alveolus

摘要： 申请书中的建议概述了一项为期五年的培训计划，以发展作为一名 心肺生物学内科医生兼科学家。应聘者是儿科讲师和儿科医生 费城儿童医院的心脏病专家。拟议的研究将在 他是心肺发展领域的领军人物爱德华·E·莫里西博士的导师。Dr。 莫里西培训了许多年轻的研究人员，其中包括几名内科科学家，他们目前 学术约会。已经成立了一个咨询委员会，以提供肺病和肺炎方面的专业知识 心血管生物学除了职业指导，从老牌到新任命的独立人士 调查人员。研究环境经过精心选择，包括对两个机构的接触 允许访问广泛的资源、核心设施和智力指导。此外，候选人将 参加教学课程和众多的职业发展研讨会，以帮助确保足够的 为独立而训练。总之，这为应聘者提供了一个独特和理想的环境 培养向心肺领域的独立内科医生兼科学家过渡的技能。 我已经确定了Wnt信号响应型肺泡上皮细胞(AT2)的一个亚群，称为 Axin2+AT2或AT2sAxin2，在肺泡形成过程中表现出增强的干细胞特征(Frank DB 等人的研究。细胞报告。2016年11月22日；17(9)：2312-2325)。此外，Axin2AT2s的转录组也高度 富含对血管发育和细胞外基质产生至关重要的基因 互动。这项提议的目标不仅是进一步描述人类胚胎干细胞的祖细胞群体 但也要研究它协调肺泡上皮和内皮生长的机制 在肺泡的发生和再生过程中。因此，该提案将涉及这些进程 有两个最重要的目的：1)检测Wnt配体对肺泡上皮细胞自我更新的调节 2)确定和描述Wnt信号和Wnt信号反应的肺泡的作用 发育和再生肺泡上皮血管壁龛中的祖细胞群体。 好了！ 本申请中提出的培训计划和研究将提供关键的工具、技能和科学 成为儿科心肺领域的内科科学家的专业知识，相对研究较少和 儿科研究资金不足的领域。儿科PH和发育性肺部疾病尚无治愈方法 例如BPD。因此，对肺泡上皮祖细胞或干细胞的鉴定和鉴定可以 为治疗和肺生长提供新的靶点。

ABSTRACT: The proposal in this application outlines a five-year training program for the development of a career as a physician-scientist in cardiopulmonary biology. The candidate is an Instructor of Pediatrics and a pediatric cardiologist at the Children’s Hospital of Philadelphia. The proposed research will be carried out under the mentorship of Dr. Edward E. Morrisey, Ph.D., a leader in the field of cardiopulmonary development. Dr. Morrisey has trained numerous young investigators including several physician-scientists who currently hold academic appointments. An advisory committee has been assembled to provide expertise in pulmonary and cardiovascular biology in addition to career guidance from well-established to newly appointed independent investigators. The research environment has been carefully selected to include exposure to two institutions allowing access to extensive resources, core facilities, and intellectual guidance. In addition, the candidate will be participating in didactic courses and numerous professional development seminars to help ensure adequate training for independence. Together, this provides a unique and ideal environment for the candidate to develop the skills to transition to an independent physician-scientist in the cardiopulmonary field. I have identified a subpopulation of Wnt signaling-responsive type 2 alveolar epithelial cells (AT2s), called Axin2+ AT2s or AT2sAxin2, which exhibit enhanced stem cell characteristics during alveologenesis (Frank DB et al. Cell Reports. 2016 Nov 22;17(9):2312-2325). In addition, the transcriptome of Axin2 AT2s are highly enriched for genes that are essential for vascular development and extracellular matrix production and interactions. The goal of this proposal is to not only further characterize this progenitor cell population in the alveolus but also examine the mechanism by which it orchestrates alveolar epithelial and endothelial growth during generation and regeneration of the alveolus. Therefore, the proposal will address these processes with two overriding aims: 1) Examine the regulation of alveolar epithelial cell self-renewal by Wnt ligand secretion; and 2) Identify and delineate the role of Wnt signaling and Wnt signaling-responsive alveolar progenitor cell populations in the epithelial-vascular niche of the developing and regenerating alveolus. ! The training program and research proposed in this application will provide critical tools, skills, and scientific expertise to become a physician-scientist in the pediatric cardiopulmonary field, a relatively understudied and underfunded area of pediatric research. There is no cure for pediatric PH and developmental lung diseases such as BPD. Thus, the identification and characterization of alveolar epithelial progenitor or stem cells could provide novel targets for therapy and lung growth.