The Identification and Study of a Lung Mesenchymal Stem Cell

这份修订后的提案描述了一项为期5年的培训计划，目的是在 医学。首席研究员已经完成了肺部和危重疾病的临床/研究奖学金 凯尔在波士顿大学工作，现在正在过渡到独立调查员的职业生涯。艾伦 Fine.M.D.将指导首席研究员的科学发展。Fine博士是公认的 肺部生物学专业，具有丰富的博士后培养经验和研究生培养经验。为了确保 这项建议的目的达到了首席研究员肯·沃尔什博士的专业知识， 并组建了一个顾问团队，其中包括惠灵顿·卡多佐，医学博士，博士，公认的 肺发育，以及干细胞生物学专家彼得·奎森伯里博士。这样做的总体目标是 建议研究从胚胎小鼠肺中分离出的一种新发现的细胞类型，它具有以下特征 间充质干细胞/祖细胞。这些细胞缺乏成熟间充质细胞的特征，可以 在培养过程中分化为平滑肌、脂肪和软骨。虽然总的频率，和具体的 这些细胞的表型尚未确定，免疫表型数据已将这些细胞定位于 肺组织中CD45(-)、细胞角蛋白(-)、CD31(-)SP细胞成分。值得注意的是，维持 这些处于未分化状态的细胞尚不清楚；然而，我们的试点数据表明FOXO在其中扮演了一个角色 转录因子亚家族。这些发现使我们得出了以下假设：包含 胚胎肺是间充质干细胞。这些细胞位于CD45(-)细胞角蛋白(-)CD31(-)SP内 组分，具有独特的表型，是分化间充质细胞类型的前体，其 分化状态受转录因子FOXO亚家族的调控。为了测试这一点，我们建议： 1.鉴定胚胎肺内具有间充质干/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，加上波士顿大学提供的丰富的科学环境，是 旨在使首席调查员能够达到概述的目标，推进他的科学 背景，并建立了作为独立调查员的职业生涯。

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.