Role of Oxidative Stress in Stem Cell Differentiation and Survival

描述（由申请人提供）： 干细胞移植作为冠心病终末期心肌挽救的一种潜在治疗手段，其分化潜能已引起广泛关注。然而，很少有人知道的干细胞分化的调节机制在体内，并在恶劣的条件下，如心肌梗死。心肌梗死导致局部微环境的变化并增加氧化应激，这可以调节细胞分化和存活。我们计划的长期目标是研究干细胞移植到心脏后的生物学。我们的主要假设是，氧化状态的变化在心肌干细胞分化和存活中起作用。为了验证这一假设，我们有以下具体目标：在具体目标1中，我们将在细胞培养物和活体受试者中将骨髓基质细胞分化为具有肌细胞特征的细胞，我们将使用分子技术非侵入性地跟踪这种分化，直到最近才能做到这一点。为此，我们将使用报告成像技术和光学成像。在具体目标2中，我们将研究氧化应激增加是否参与干细胞分化和存活。为此，将在细胞培养物和活体受试者（心肌梗死后）中诱导，之后将使用分子成像技术（光学成像）跟踪干细胞分化和存活。此外，我们将研究与氧化应激（即一氧化氮）相关的途径，并研究它们在干细胞分化中的作用。最后，在具体目标3中，我们将从目标1和2中学习“基因工程”干细胞，使它们更好地准备在恶劣条件下分化和生存，就像在心肌缺血和梗死状态中发现的那样。 这项资助中提出的研究将提供有关微环境在干细胞分化和存活中所起作用的宝贵信息，并可能导致新的和改进的治疗策略。 干细胞治疗为重建受损心脏提供了一个很好的机会，但我们首先需要阐明调节干细胞分化和存活的机制。在这项研究中，我们提出，特定的生物途径（即，氧化剂状态）可参与这种反应。了解这些调节干细胞存活的机制将导致更好和改进的治疗。 (End摘要）

DESCRIPTION (provided by applicant): Stem cell transplantation offers much promise as a potential treatment for myocardial salvation at the end stages of coronary artery disease (CAD), and much interest has been placed in the differentiation capacity of different population of stem cells. However, little is known about the regulatory mechanisms of stem cell differentiation in vivo, and under hostile conditions, like myocardial infarction. Myocardial infarction leads to changes in the local microenvironment and increases oxidative stress, which can regulate cellular differentiation and survival. The long-term goal of our program is to study the biology of stem cells after transplantation to the heart. Our primary hypothesis in this proposal is that changes in oxidant status play a role in stem cell differentiation and survival in the mycoardium. To test that hypothesis we have the following specific aims: in Specific Aim 1 we will differentiate bone marrow stromal cells into cells with myocyte characteristics, both in cell culture and in living subjects, and we will use molecular techniques to track this differentiation non-invasively, something that could be done until recently. For that purpose we will use reporter imaging technology and optical imaging. In Specific Aim 2, we will examine if increased oxidative stress is involved in stem cell differentiation and survival. For that, will be induced in cell culture and in living subjects (after myocardial infarction), after which stem cell differentiation and survival will be tracked using molecular imaging techniques (optical imaging). In addition, we will study pathways related to oxidative stress (i.e. nitric oxide), and examine their role in stem cell differentiation. Lastly in Specific Aim 3, we will learn from Aims 1 and 2 and "genetically engineer" stem cells so they are better prepared to differentiate and survive in hostile condition, like the one found in states of myocardial ischemia and infarction. The studies proposed in this grant will provide invaluable information on the role that the micro-environment plays in stem cell differentiation and survival and can lead to novel and improved therapeutic strategies. Stem cell therapy provides a great opportunity to re-constitute a damaged heart, but we first need to elucidate the mechanisms that regulate stem cell differentiation and survival. In this study we propose that specific biological pathways (i.e., oxidant status) can be involved in such response. Understanding these mechanisms that regulate stem cell survival will lead to better and improved therapies. (End of Abstract)