Role of Oxidative Stress in Stem Cell Differentiation and Survival

摘要：干细胞移植作为一种潜在的心肌拯救治疗方法， 在冠状动脉疾病（CAD）的终末期，并且已经将很多兴趣放在了分化上， 不同群体干细胞的能力然而，人们对这些基因的调控机制知之甚少。 干细胞分化在体内，以及在不利条件下，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 分化和生存。我们计划的长期目标是研究干细胞的生物学， 移植到心脏我们在这个提议中的主要假设是，氧化状态的变化起着重要作用。 在干细胞分化和心肌中的sun/ival中的作用。为了验证这一假设，我们有以下内容 具体目标：在具体目标1中，我们将骨髓基质细胞分化为具有肌细胞的细胞， 特征，无论是在细胞培养和活体，我们将使用分子技术来跟踪这一点， 非侵入性的分化，直到最近才能做到。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，我们将检查是否增加了氧化 应激参与干细胞分化和凋亡。为此，将在细胞培养和活体中诱导 受试者（心肌梗死后），之后将使用跟踪干细胞分化和存活 分子成像技术（光学成像）。此外，我们将研究与氧化有关的途径， 应激（即一氧化氮），并检查它们在干细胞分化中的作用。在第三阶段，我们将 从目标1和2中学习，“基因工程”干细胞，使它们更好地准备分化， 在恶劣的条件下生存，就像在心肌缺血和梗死状态下发现的那样。 这项赠款中提出的研究将提供有关微环境作用的宝贵信息， 在干细胞分化和存活中发挥作用，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sun/ival的机制。在这项研究中，我们提出， 特定的生物学途径（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疗法。

ABSTRACT: 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 ceil 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 sun/ival 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 ceil differentialton and sun/ival. 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 microenvironment 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 sun/ival. 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.