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（由适用提供）：这些研究的总体目标是定义造血干型干细胞（HSPC）介导的在压力期间介导的免疫抑制的机制。压力对免疫系统产生了巨大影响，因此有助于多种疾病的发作和进展，包括免疫疾病，感染和癌症。但是，应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在调节免疫和炎症反应中起着重要作用。我们利用一种限制应力的小鼠模型，该模型已被广泛使用，包括在我们的实验室和其他人中，研究压力对免疫调查的影响。使用此模型，我们发现HSPC可以防止应激诱导的脾细胞凋亡。我们发现IL-4对于HSPC对应激诱导的脾细胞还原的受保护作用至关重要。据我们所知，这是HSPC在压力诱导的免疫调查的发病机理中的一种新的新作用。然而，尚不清楚HSPC调节应力诱导的免疫复杂的机制。目前，我们尚不了解HSPC在压力引起的免疫抑制中的作用，也不了解HSPC介导的IL-4信号传导对应激过程中淋巴细胞凋亡的影响。根据我们的新发现，我们假设HSPC通过调节IL-4信号传导来防止应力诱导的免疫抑制。我们提出以下两个旨在检验这一假设的目标。 AIM 1将定义 应力诱导的免疫抑制中的HSPC。我们假设HSPC可以防止压力诱导的免疫抑制。要发表这一假设，将野生型小鼠作为媒介物施用HSPC或热杀死的HSPC，然后在不同时间段内受到约束应力。我们将确定HSPC对应激后HSPC对淋巴细胞凋亡和免疫调查的影响。 AIM 2将研究HSPC对应激后IL-4介导的凋亡信号传导的影响。我们的假设是HSPC可以通过IL-4介导的信号传导来预防应激诱导的淋巴细胞凋亡。我们将管理HSPC和IL-4中和抗体，然后受试者在不同的时间段中限制应力。将评估HSPC介导的IL-4信号传导对淋巴细胞凋亡的影响。为了进一步定义IL-4介导的信号传导有助于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基因敲除小鼠来验证IL-4在此过程中的作用。我们的研究应描绘出免疫抑制中HSPC介导的信号传导的机制，并为开发有效抵抗压力的对策提供新的信息。