The Identification and Study of a Lung Mesenchymal Stem Cell

描述(由申请人提供)： 这份修订后的提案描述了一项为期5年的医学学术生涯发展培训计划。这位首席研究员已经在波士顿大学完成了肺和重症护理的临床/研究奖学金，现在正在过渡到独立研究员的职业生涯。Alan Fine.M.D.将指导首席研究员的科学发展。Fine博士是肺部生物学领域公认的领导者，在培养博士后研究员和研究生方面拥有丰富的经验。为了确保这项建议的目标得以实现，首席研究员征集了肯·沃尔什博士的专业知识，并组建了一个顾问团队，其中包括公认的肺部发育领先者惠灵顿·卡多佐医学博士和干细胞生物学专家彼得·奎森伯里博士。这项建议的总体目标是研究一种从胚胎小鼠肺中分离出来的具有间充质干细胞/祖细胞特征的新发现的细胞类型。这些细胞缺乏成熟间充质细胞的特征，在培养过程中可以分化为平滑肌、脂肪和软骨。虽然这些细胞的总体频率和特定表型尚未确定，但免疫表型数据已将这些细胞定位于肺中CD45(-)、细胞角蛋白(-)、CD31(-)SP细胞部分。值得注意的是，维持这些细胞处于未分化状态的分子机制尚不清楚；然而，我们的初步数据表明，FOXO转录因子亚家族发挥了作用。这些发现使我们得出以下假设：胚胎肺中含有间充质干细胞。这些细胞存在于CD45(-)细胞角蛋白(-)CD31(-)SP组分中，具有独特的表型，是分化间充质细胞类型的前体，它们的分化状态受转录因子FOXO亚家族的调节。为了测试这一点，我们建议：1.鉴定胚胎肺中包含的具有间充质干细胞/祖细胞活性的细胞。2.评价这些细胞向成熟肺间充质细胞分化的体内能力。3.进一步探讨FOXO亚家族在调控这些细胞分化状态中的作用。这一建议，再加上波士顿大学提供的丰富的科学环境，旨在使首席调查员能够实现所述目标，提升其科学背景，并建立作为独立调查员的职业生涯。(摘要结束)

DESCRIPTION (provided by applicant): This revised proposal describes a 5-year training program for the development of an academic career in Medicine. The principal investigator has completed a clinical/research fellowship in Pulmonary and Critical Care at Boston University, and is now transitioning to a career as an independent investigator. Alan Fine.M.D. will mentor the principal investigator's scientific development. Dr Fine is a recognized leader in lung biology, and has extensive experience training post-doctoral fellows, and graduate students. To ensure the Aims of this proposal are met the principal investigator has enlisted the expertise of Ken Walsh, PhD, and has put together a team of advisors that include Wellington Cardoso,MD, PhD, a recognized leader in lung development, and Dr Peter Quesenberry, an expert in stem cell biology. The overall objective of this proposal is to study a newly identified cell type isolated from the embryonic murine lung that has features of a mesenchymal stem/progenitor. These cells lack characteristics of mature mesenchymal cells, and can differentiate to smooth muscle, fat and cartilage during culture. While the overall frequency, and specific phenotype of these cells has yet to be determined, immuno-phenotyping data has localized these cells to the CD45(-),cytokeratin(-),CD31 (-) SP cell fraction of the lung. Notably, the molecular mechanisms maintaining these cells in an undifferentiated state are unknown; however, our pilot data suggest a role for the Foxo subfamily of transcription factors. These findings have led us to the following hypothesis: Contained with the embryonic lung are mesenchymal stem cells. These cells reside within the CD45(-)cytokeratin(-)CD31(-) SP fraction, have a unique phenotype, serve as precursors to differentiated mesenchymal cell types, and their state of differentiation is regulated by the Foxo subfamily of transcription factors. To test this we propose to: 1. Identify the cells contained within the embryonic lung that possess mesenchymal stem/progenitor activity. 2. Evaluate the in vivo capacity of these cells to differentiate to mature lung mesenchymal cell types. 3. Further explore the role of the Foxo subfamily in controlling the differentiation state of these cells. Together this proposal, coupled with the rich scientific environment offered at Boston University are designed to enable the principal investigator to meet the objectives outlined, advance his scientific background, and establish a career as an independent investigator. (End of Abstract)