Role of Hematopoietic Stem Progenitor Cells in Stress-Induced Apoptosis

造血干祖细胞在应激诱导的细胞凋亡中的作用

• 批准号: 8874534
• 负责人: DELING YIN
• 金额: $ 33.85万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874534
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adoptive Transfer; Affect; Animals; Apoptosis; Apoptotic; Autoimmune Diseases; CD34 gene; Chronic stress; Development; Dexamethasone; Disease; Epidemiologic Studies; Glucocorticoids; Goals; Health; Heating; Hematopoietic; Hormones; Human; Immune System Diseases; Immune response; Immune system; Immunosuppression; Infection; Inflammatory Response; Interleukin-4; Knockout Mice; Laboratories; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Pathogenesis; Pharmaceutical Preparations; Play; Predisposition; Process; Production; Psychological Stress; Regulation; Research; Role; Signal Transduction; Splenocyte; Stem cells; Stress; Testing; Text; Time; Wild Type Mouse; apoptosis in lymphocytes; base; cytokine; human disease; immune function; killings; mouse model; neutralizing antibody; novel; prevent; protective effect; public health relevance; receptor-mediated signaling; restraint stress; stem

 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.

 描述（由申请人提供）：这些研究的总体目标是确定造血干祖细胞（HSPC）在应激期间介导的抑制免疫的潜在机制。然而，压力影响免疫系统的机制仍有待阐明，我们和其他人的最新证据表明，HSPC 发挥着重要作用。我们利用约束应激小鼠模型来研究应激对免疫反应的影响，该模型已在我们的实验室和其他实验室中广泛使用。我们发现 IL-4 对于 HSPC 对应激引起的脾细胞减少的保护作用至关重要。然而，HSPCs 调节应激诱导的免疫抑制的机制目前尚不清楚，我们也不了解 HSPCs 在应激诱导的免疫抑制中的作用，也不了解 HSPCs 的作用。根据我们的新发现，HSPC 通过调节 IL-4 信号传导来预防应激诱导的免疫抑制，我们提出以下两个目标来检验这一假设。的作用 HSPC 在应激诱导的免疫抑制中的作用。为了证明这一假设，野生型小鼠将被施用 HSPC 或热灭活的 HSPC 作为载体，然后在不同的时间段内受到约束应激。我们将确定 HSPC 对应激后淋巴细胞凋亡和免疫反应的影响，目标 2 将研究 HSPC 对应激后 IL-4 介导的细胞凋亡信号传导的影响。 HSPC 通过 IL-4 介导的信号传导来防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，然后让小鼠在不同的时间段内抑制应激，观察 HSPC 介导的 IL-4 信号传导对淋巴细胞的影响。为了进一步明确 IL-4 介导的信号传导对 HSPC 对应激诱导的淋巴细胞凋亡的保护作用的机制，我们将利用 IL-4 敲除小鼠来验证 IL-4 在此过程中的作用。我们的研究应该阐明 HSPC 介导的免疫抑制信号传导机制，并为开发有效的应激对策提供新的信息。