INJURED LUNG AND ITS INFLUENCE ON MARROW CELL PHENOTYPE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目将研究受损肺细胞和骨髓细胞之间的细胞间通讯，以及这种通讯有助于基于骨髓细胞的肺修复肺损伤的机制。 我们实验室的研究表明，成年骨髓细胞可以回到受损的小鼠肺，并参与肺细胞的恢复。 我们假设，损伤的肺细胞诱导骨髓细胞的表观遗传修饰的释放从肺细胞和随后的肺细胞衍生的微泡的骨髓细胞的摄取，从而诱导骨髓细胞承担肺细胞表型。 具体目标是：1.定义吸收肺源性微泡的骨髓细胞群，重点是全骨髓细胞、各种骨髓源性分化细胞和纯化的造血干/祖细胞，并定义这些表型变化的持续性。2.确定肺源性微泡如何进入骨髓细胞以及它们如何影响这些细胞的表型。 3.明确细胞周期对骨髓细胞吸收肺源性微泡能力的影响。 4.确定移植已经吸收肺源性微泡或微泡本身的骨髓细胞是否参与肺动脉高压小鼠模型的发病机制。 最终，我们希望证明骨髓细胞具有足够的修复特性，为目前有效治疗方法很少的肺部疾病提供新的治疗选择。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This project will examine cell-to-cell communication between injured lung cells and bone marrow cells and mechanisms by which this communication aids in marrow cell-based lung repair of lung injury. Research from our laboratory has demonstrated that adult bone marrow cells home to injured murine lung and participate in the restoration of lung cells. We hypothesize that injured lung cells induce epigenetic modifications of marrow cells by release from lung cells and subsequent uptake by marrow cells of lung cell-derived microvesicles, thereby inducing marrow cells to assume a lung cell phenotype. The specific aims are to: 1. Define marrow cell populations which take up lung-derived microvesicles, focusing on whole bone marrow cells, various marrow-derived differentiated cells and purified hematopoietic stem/progenitor cells, and define the persistence of these phenotypic changes. 2. Determine how lung-derived microvesicles gain entry into marrow cells and how they influence the phenotype of these cells. 3. Define the influence of cell cycle on the ability of marrow cells to take up lung-derived microvesicles. 4. Determine if transplantation of marrow cells that have taken up lung-derived microvesicles or microvesicles themselves participate in the pathogenesis of murine models of pulmonary hypertension. Ultimately, we wish to demonstrate that marrow cells possess sufficient reparative properties to provide a novel therapeutic option for pulmonary diseases with few currently effective treatments.