Endothelial Progenitor Cells for Lung Repair

描述（由申请人提供）：这个为期两年的职业提升奖的重点是为医生和科学家候选人提供新的工具和机会，以完成用于微血管修复的人类干细胞群体的定向分化和优化。血管基础设施是毁灭性肺损伤恢复的重要组成部分，是组织工程努力成功的组成部分。成功构建工程微血管网络的一个主要挑战是缺乏现成可用的内皮细胞群。如果要避免危重患者的免疫抑制和移植物抗宿主问题，这是一个必不可少的因素，这些危重患者可能会接受这些工程网络作为抢救治疗。这两个特定的目标将集中在CD14+外周血单核细胞（Aim 1）和CD34+骨髓干细胞祖细胞（Aim 2）的信号通路和细胞周期控制方法的操纵上，以加速定向分化为内皮表型，优化血管生成。这将通过使用慢病毒基因转导来完成。这些细胞在来源于人成纤维细胞的三维基质中的活力和功效，以及在免疫缺陷NOD-scid IL2Rg-/- (NOG)小鼠的移植模型中进行测试。人类胚胎干细胞向微血管内皮表型的定向分化也将继续进行。这些研究将为未来在组织工程微血管网络中干细胞群体的研究奠定基础，以促进新的薄壁组织的形成！灾难性肺部疾病后的增长。在约翰霍普金斯大学Sidney Kimmel综合癌症中心的赞助实验室为转化干细胞生物学提供了一个优秀的培训环境。作为干细胞研究领域的领导者，赞助商拥有十年的经验，一流的高级研究人员团队，最先进的设备和小鼠移植核心设施，这一切都是由于机构对这一研究领域的强烈和有远见的承诺而成为可能。公共卫生影响：危及生命的肺部损伤可破坏正常组织。恢复的能力依赖于微小的营养血管网络，这些血管允许新肺生长。这个职业提升奖将为在重症监护室照顾肺损伤儿童的医生提供干细胞方面的特殊培训。利用在世界级干细胞中心学到的技术，有可能促进新血管的发育，加快肺部从严重疾病中恢复的速度和成功率。

DESCRIPTION (provided by applicant): This 2-year Career Enhancement Award is focused on providing the physician-scientist candidate with new tools and opportunities to accomplish the directed differentiation and optimization of human stem cell populations for use in microvascular restitution. Vascular infrastructure is an essential ingredient for recovery from devastating lung injury, and is integral to the success of tissue engineering efforts. One major challenge to the successful execution of an engineered microvascular network is the lack of a readily usable endothelial cell population. This is an essential ingredient if immunosuppression and graft versus host issues are to be avoided in the already critically ill patients that may receive these engineered networks as a rescue therapy. The two specific aims will focus on the manipulation of signaling pathways and cell cycle control methods in CD14+ peripheral blood mononuclear cells (Aim One) and CD34+ bone marrow stem-progenitor cells (Aim Two) in order to speed directed differentiation to an endothelial phenotype that is optimized for vasculogenesis. This will be accomplished through the use of lentiviral gene transduction. The viability and efficacy of these cells in 3-D matrices derived from human fibroblasts, and in transplantation models in immunodeficient NOD-scid IL2Rg-/- (NOG) mice will be tested. The directed differentiation of human embryonic stem cells to a microvascular endothelial phenotype will also be pursued. These investigations will lay the groundwork for future studies on stem cell populations in tissue-engineered microvascular networks to facilitate new parenchyma! growth following catastrophic pulmonary illness. The sponsor's lab in the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University provides an outstanding training environment for translational stem cell biology. The sponsor's decade of experience as a leader in stem cell research, a first rate team of senior investigators, state-of-the-art equipment, and a mouse transplantation core facility are all made possible by intense and far-sighted institutional commitment to this field of inquiry. PUBLIC HEALTH IMPACT: Life-threatening injury to the lung can destroy normal tissues. The capacity to recuperate depends upon networks of tiny nutrient blood vessels that allow new lung to grow. This Career Enhancement Award will provide special training in stem cells to a physician caring for children with lung injury in the intensive care unit. Using techniques learned in a world-class stem cell center, it may be possible to encourage the development of new blood vessels and increase the pace and success of lung recovery from severe illness.