Interleukin-1 (IL-1) Receptor-Mediated Modulation of Serotonin Transporters

白细胞介素 1 (IL-1) 受体介导的血清素转运蛋白调节

• 批准号: 7990615
• 负责人: Chongbin Zhu
• 金额: $ 19.39万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990615
• 关键词: Acute; Address; Alleles; Animal Model; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Autistic Disorder; Behavior; Biological Response Modifiers; Brain; Breeding; Cell Line; Cells; Collaborations; Core Facility; DNA; Data; Development; Disease; Endotoxins; Exons; Future; Generations; Genes; Genotype; Germ Lines; Goals; Homeostasis; Human; Human Volunteers; Immune system; Immunohistochemistry; In Vitro; Inflammatory; Injection of therapeutic agent; Interleukin-1; Interleukin-1 Receptors; Interleukin-6; Knock-out; Knockout Mice; Laboratories; Link; Lipopolysaccharides; Mediating; Memory impairment; Mental Depression; Methods; Mood Disorders; Moods; Mus; Neurons; Neurotransmitters; Pathogenesis; Peripheral; Pharmaceutical Preparations; Production; Recycling; Regulation; Risk; Role; Serotonin; Serum; Signal Pathway; Signal Transduction; Site; Social Interaction; Southern Blotting; Stress; Synapses; Synaptosomes; Syndrome; Tail Suspension; Technology; Testing; Transgenic Mice; Transgenic Organisms; Validation; Wild Type Mouse; anakinra; animal breeding; behavior test; blastocyst; cytokine; immune activation; in vivo; insight; interest; knockout animal; mouse model; neurobehavior; neuropsychiatry; novel; presynaptic; programs; public health relevance; receptor; response; serotonin transporter; stressor; trait; transmission process; uptake; vector

DESCRIPTION (provided by applicant): The role of pro-inflammatory cytokines in the pathogenesis of neuropsychiatric disorders has drawn a significant interest over the last decade. Cytokines are also known to modulate serotonergic activity. The 5-HT transporter (SERT), one of the major targets of antidepressants, which supports 5-HT inactivation and recycling, is tightly regulated by multiple signaling pathways including those stimulated by the proinflammatory cytokines IL-1¿ and TNF-a. We have shown that IL-1¿ stimulates SERT activity in a raphe cell line as well as in mouse synaptosomes ex vivo. Our preliminary data now demonstrate that peripheral injection of LPS induces an acute (1hr) increase in central 5-HT uptake in wild type mice but not in IL-1R knockouts. We hypothesizes that a presynaptic IL-1Rs communicates local and systemic inflammatory stress (and other stressors) via modulation of SERT activity. As the distribution of IL-1Rs in the CNS is not limited to the raphe neurons and their terminals, dissecting the contribution of serotonergic modulation will require restricted elimination of IL-1¿ action. Thus, the objectives of the current proposal are to generate IL-1R floxed mice, further develop serotonergic neuron specific IL-1R knockout using FloxP/Cre technologies and to characterize the 5-HT homeostasis and related behaviors in these animals. My hypothesis is that deletion of IL-1 receptors in the raphe serotonergic neurons will eliminate the impact of IL-1¿ / LPS on central SERT activity. The validation of this hypothesis will (1) provide critical data for an enlarged study examining cytokine-5HT interactions and (2) help to advance our understanding towards the contribution of modulated 5HT signaling networks to depression-like traits that emerge in sickness syndrome paradigms. To achieve the goal of this proposal, we plan to conduct the following studies: 1. Generate floxed IL-1R mice; 2 Develop and characterize serotonergic neuron-specific IL-1R knockout mice. The essential goal of this project is to achieve germ-line transmission of a floxed allele of the IL-1R with no inherent impact on native IL-1R production in the absence of a Cre driver, and eventually develop conditional IL-1R knockouts. Together, these efforts support the long-term goal of elucidating in vivo mechanisms through which pro-inflammatory cytokines modulate brain function and behavior. PUBLIC HEALTH RELEVANCE: This project investigates the link between Immunological challenges and a key gene controlling the neurotransmitter serotonin for insights into mechanisms that may impact risk for mood disorders including depression, anxiety and autism. This project specifically investigates the immune mediator Interleukin-1 and its receptor in regulation of the brain serotonin transporter (SERT), a major target for antidepressant medications. These studies seek to develop a novel transgenic mouse model that can address the sensitivity of brain serotonin neurons and SERT to IL-1¿ and establish an experimental framework to more precisely link the immune system to mood regulatory mechanisms.

描述(由申请人提供)：在过去的十年里，促炎细胞因子在神经精神障碍发病机制中的作用引起了人们的极大兴趣。细胞因子也是已知的调节5-羟色胺能活动的物质。5-羟色胺转运体(SERT)是抗抑郁药物的主要靶点之一，它支持5-羟色胺的失活和再循环，受到多种信号通路的严格调控，其中包括由促炎细胞因子IL-1和TNF-a刺激的信号通路。我们已经证明，IL-1在体外刺激中缝细胞系和小鼠突触体内的SERT活性。我们的初步数据现在表明，外周注射脂多糖可诱导野生型小鼠中枢5-羟色胺摄取急剧增加(1小时)，但不能诱导IL-1R基因敲除。我们假设突触前IL-1RS通过调节SERT活性传递局部和全身炎症应激(和其他应激源)。由于IL-1Rs在中枢神经系统中的分布并不局限于中缝神经元及其终末，因此剖析5-羟色胺能调节的作用需要限制IL-1的作用。因此，本研究的目标是建立IL-1R小鼠，利用FloxP/Cre技术进一步开发5-羟色胺能神经元特异性IL-1R基因敲除，并研究这些动物体内5-羟色胺的动态平衡及相关行为。我的假设是，中缝5-羟色胺能神经元中IL-1受体的缺失将消除IL-1？/内毒素对中枢SERT活性的影响。这一假说的验证将(1)为检验细胞因子-5-羟色胺相互作用的扩大研究提供关键数据，(2)有助于推进我们对调制的5-羟色胺信号网络对疾病综合征范例中出现的抑郁症样特征的贡献的理解。为了实现这一建议的目标，我们计划进行以下研究：1.建立IL-1R小鼠；2.建立和鉴定5-羟色胺能神经元特异性IL-1R基因敲除小鼠。这个项目的基本目标是在没有CRE驱动程序的情况下实现IL-1R的等位基因的胚系传播，而不对天然IL-1R的产生产生固有影响，并最终开发有条件的IL-1R敲除。总之，这些努力支持了阐明体内促炎细胞因子调节大脑功能和行为的机制的长期目标。 公共卫生相关性：该项目调查免疫挑战和控制神经递质5-羟色胺的关键基因之间的联系，以深入了解可能影响包括抑郁、焦虑和自闭症在内的情绪障碍风险的机制。该项目专门研究免疫介质白介素1及其受体在脑5-羟色胺转运体(SERT)调节中的作用，SERT是抗抑郁药物的主要靶点。这些研究试图开发一种新型的转基因小鼠模型，该模型可以解决大脑5-羟色胺神经元和SERT对IL-1的敏感性，并建立一个实验框架，以更精确地将免疫系统与情绪调节机制联系起来。