COBRE PROJ 10: VSEL AND BRAIN REGENERATION IN A MURINE MODEL OF SLEEP APNEA

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 干细胞提供了一个新的潜在来源，以取代死亡的神经元和支持组织在脑损伤的慢性缺血，如在睡眠呼吸暂停（SA）。对动物和短期人类骨髓移植的一些研究已经证明，骨髓细胞提供了神经元的来源，并且可以修复脑损伤（例如，在中风期间）。这种功能改善的机制目前是密集研究的焦点，需要新的研究方法来评估这些策略的有效性。阐明干细胞相关的再生机制对于开发有效的基于干细胞的疗法至关重要，这些疗法可以延长患有可通过组织再生治疗的疾病的患者的寿命。一种这样的疾病是由于睡眠呼吸暂停引起的缺氧引起的慢性脑损伤。 最近，我们已经从成年鼠骨髓（BM）中纯化了稀有（约0.01%的BMMNC）CXCR 4+、Oct-4+ SSEA-1+、Sca-1+ lin-CD 45-非常小的胚胎样（VSEL）干细胞的同质群体。 直接电子显微镜分析显示，这些细胞很小（约2-4 mm），具有由细胞质窄边包围的大核，并含有胚胎干细胞典型的开放型染色质（常染色质）。 基于我们的初步数据，提出了一种新的假设，即CXCR 4+外胚层衍生的VSEL池在早期发育期间沉积在BM中。 这些细胞随后充当干细胞的储备移动的库，其可被动员到外周血中并在脑再生中发挥重要作用-其中它们被SDF-1梯度化学吸引。 此外，假设这些循环VSEL的骨髓池中与年龄相关的减少可能有助于中枢神经系统（CNS）的老化，导致较不有效的修复。 为了调查这些问题，提出了四个具体目标（目标见进展一节）。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Stem cells provide a novel potential source to replace dead neurons and supporting tissue in brain damaged by chronic ischemia as seen for example in sleep apnea (SA). Some investigations of animals and short-term human bone marrow transplants have demonstrated that bone marrow cells provide a source of neurons and can repair brain damage (e.g., during stroke). The mechanisms of this functional improvement are currently the focus of intense research, creating a need for new study methodologies to assess the effectiveness of such strategies. Elucidation of stem cell-related mechanisms of regeneration is crucial to developing effective stem cell-based therapies that could extend the lifespan of patients with diseases that are treatable by tissue regeneration. One such disorder is chronic brain damage due to hypoxia resulting from sleep apnea. Recently we have purified from adult murine bone marrow (BM) a homogenous population of rare (~0.01% of BMMNC) CXCR4+, Oct-4+ SSEA-1+, Sca-1+ lin- CD45- very small embryonic-like (VSEL) stem cells. Direct electron microscopical analysis revealed that these cells are small (~2-4 mm), possess large nuclei surrounded by a narrow rim of cytoplasm, and contain open-type chromatin (euchromatin) that is typical for embryonic stem cells. Based on our preliminary data, a novel hypothesis is presented that the pool of CXCR4+ epiblast derived VSEL is deposited in the BM during early development. These cells subsequently serve as a reserve mobile pool of stem cells that may be mobilized into peripheral blood and play an important role in brain regeneration - where they are chemoattracted by an SDF-1 gradient. Furthermore, it is hypothesized that an age-related decrease in the marrow pool of these circulating VSEL may contribute to aging of the central nervous system (CNS), resulting in less effective repair. To investigate these issues, four specific aims are proposed (see Progress Section for aims).