Role of Hematopoietic Stem Progenitor Cells in Stress-Induced Apoptosis

 描述(申请人提供)：这些研究的总体目标是确定在应激状态下造血干细胞(HSPC)介导免疫抑制的潜在机制(S)。压力对免疫系统有巨大的影响，从而导致各种疾病的发生和发展，包括免疫紊乱、感染和癌症。然而，应激影响免疫系统的机制仍有待阐明。最近来自我们和其他人的证据表明，HSPC在免疫和炎症反应的调节中发挥着重要作用。我们利用束缚应激的小鼠模型来研究应激对免疫反应的影响，该模型已被广泛应用于我们的实验室和其他实验室。利用这一模型，我们发现HSPC可以防止束缚应激诱导的脾细胞凋亡。我们发现IL-4在HSPC对应激诱导的脾细胞减少的保护作用中是必不可少的。就我们所知，这是HSPC在应激诱导免疫反应的发病机制中的一个新的和新的角色。然而，HSPC调节应激诱导的免疫抑制的机制尚不清楚。目前，我们还不清楚HSPC在应激诱导的免疫抑制中的作用，也不清楚HSPC介导的IL-4信号在应激过程中对淋巴细胞凋亡的影响。基于我们的新发现，我们假设HSPC通过调节IL-4信号来防止应激诱导的免疫抑制。我们提出了以下两个目的来检验这一假说。目标1将定义 HSPC在应激诱导免疫抑制中的作用。我们假设HSPC可以保护机体免受应激引起的免疫抑制。为了验证这一假说，野生型小鼠将被给予HSPC或热灭活HSPC作为载体，然后在不同的时间段受到束缚应激。我们将确定HSPC在应激后对淋巴细胞凋亡和免疫反应的影响。目的2研究HSPC在应激后IL-4介导的细胞凋亡信号转导中的作用。我们的假设是HSPC通过IL-4介导的信号转导来阻止应激诱导的淋巴细胞凋亡。我们将给予HSPC和IL-4中和抗体，然后对小鼠进行不同时间的束缚应激。将评估HSPC介导的IL-4信号在淋巴细胞凋亡中的作用。为了进一步明确IL-4介导的信号转导机制在HSPC对应激诱导的淋巴细胞凋亡的保护作用中的作用机制，我们将利用IL-4基因敲除小鼠来验证IL-4在这一过程中的作用。我们的研究将阐明HSPC介导的免疫抑制信号的机制，并为开发有效的应激对策提供新的信息。

 DESCRIPTION (provided by applicant): The overall goal of these studies is to define the mechanism(s) underlying hematopoietic stem-progenitor cells (HSPCs) mediated immune suppression during stress. Stress has dramatic impacts on the immune system and consequently contributes to the onset and progression of a variety of diseases, including immune disorders, infections, and cancer. However, the mechanisms by which stress affects the immune system remain to be elucidated. Recent evidence from us and others has shown that HSPCs play an important role in the regulation of immune and inflammatory responses. We utilize a mouse model of restraint stress, which has been widely used, including in our laboratory and others, to study the effects of stress on immune responses. Using this model we discovered that HSPCs prevent restraint stress-induced splenocyte apoptosis. We found that IL-4 is essential for the protective effects of HSPCs on splenocyte reduction induced by stress. To the best of our knowledge, this is a new and novel role for HSPCs in the pathogenesis of stress-induced immune responses. However, the mechanisms by which HSPCs regulate stress-induced immune suppression are not known. At present, we do not understand the role of HSPCs in immune suppression induced by stress, nor do we understand the effect of HSPC-mediated IL-4 signaling on lymphocyte apoptosis during stress. Based on our novel findings, we hypothesize that HSPCs prevent stress-induced immune suppression by modulating IL-4 signaling. We propose the following two aims to test this hypothesis. Aim 1 will define the role of HSPCs in stress-induced immune suppression. We hypothesize that HSPCs protect from immune suppression induced by stress. To text this hypothesis, wild type mice will be administered HSPCs or heat-killed HSPCs as vehicle, and then subjected to restraint stress for different time periods. We will determine the effect of HSPCs on lymphocyte apoptosis and immune responses following stress. Aim 2 will investigate the effect of HSPCs on IL-4-mediated apoptotic signaling following stress. Our hypothesis is that HSPCs prevent stress-induced lymphocyte apoptosis though IL-4-mediated signaling. We will administer HSPCs and IL-4 neutralizing antibody, and then subject mice to restraint stress for different time periods. The effect of HSPC-mediated IL-4 signaling on lymphocyte apoptosis will be evaluated. To further define the mechanism by which IL-4-mediated signaling contributes to the protective effect of HSPCs on stress-induced lymphocyte apoptosis, we will utilize IL-4 knockout mice to verify the role of IL-4 in this process. Our studies should delineate the mechanisms underlying HSPC-mediated signaling in immune suppression and provide novel information for the development of effective countermeasures against stress.