The Identification and Study of a Lung Mesenchymal Stem Cell

本修订提案描述了一个为期5年的培训计划，以发展学术生涯， 药主要研究者已完成肺部和危重病的临床/研究奖学金 护理在波士顿大学，现在正在过渡到职业生涯作为一个独立的调查员。艾伦 精细医学博士将指导首席研究员的科学发展Fine博士是公认的 肺生物学，并具有丰富的博士后和研究生培养经验。确保 为了达到该建议的目的，主要研究者已经招募了Ken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，公认的领导者， 肺发育，以及干细胞生物学专家Peter Quesenberry博士。本报告的总体目标 一项研究计划是研究一种新发现的从小鼠胚胎肺中分离出来的细胞类型， 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， 在培养过程中分化为平滑肌、脂肪和软骨。虽然总体频率和具体 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 肺内CD 45（-）、细胞角蛋白（-）、CD 31（-）SP细胞比例。值得注意的是， 这些未分化状态的细胞是未知的;然而，我们的试验数据表明Foxo 转录因子亚家族。这些发现使我们得出以下假设： 胚胎肺是间充质干细胞。这些细胞位于CD 45（-）细胞角蛋白（-）CD 31（-）SP内 部分，具有独特的表型，作为分化的间充质细胞类型的前体， 分化状态受转录因子Foxo亚家族调节。为了检验这一点，我们建议： 1.鉴定胚胎肺中含有的具有间充质干细胞/祖细胞活性的细胞。 2.评价这些细胞分化为成熟肺间充质细胞类型的体内能力。 3.进一步探讨Foxo亚家族在控制这些细胞分化状态中的作用。 这项提议，加上波士顿大学提供的丰富的科学环境， 旨在使主要研究者能够实现概述的目标，推进他的科学研究， 背景，并建立一个职业生涯作为一个独立的调查。

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.