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: 8123205
• 负责人: Randy D. Blakely
• 金额: $ 23.17万
• 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/8123205
• 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; Health; 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; Receptor Gene; Recycling; Regulation; Risk; Role; Serotonin; Serum; Signal Pathway; Signal Transduction; Site; Social Interaction; Southern Blotting; Stress; Synapses; Synaptosomes; Syndrome; TNF gene; 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; receptor; receptor expression; 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）：在过去十年中，促炎细胞因子在神经精神疾病发病机制中的作用引起了人们的极大兴趣。还已知细胞因子调节孕酮能活性。5-HT转运蛋白（SERT）是抗抑郁药的主要靶点之一，支持5-HT的失活和再循环，受多种信号通路的严格调节，包括受促炎细胞因子IL-1和TNF-α刺激的信号通路。我们已经证明，IL-1？刺激SERT活性在中缝细胞系以及在小鼠突触体离体。我们的初步数据表明，外周注射LPS诱导急性（1小时）增加中央5-HT摄取野生型小鼠，但不是在IL-1 R敲除。我们假设突触前IL-1 Rs通过调节SERT活性来传递局部和全身炎症应激（以及其他应激源）。由于IL-1受体在CNS中的分布并不局限于中缝神经元及其末梢，因此要分析IL-1受体调节的作用需要限制性地消除IL-1受体的作用。因此，目前的建议的目的是产生IL-1 R floxed小鼠，进一步开发使用FloxP/Cre技术的多巴胺能神经元特异性IL-1 R敲除，并表征这些动物中的5-HT稳态和相关行为。我的假设是，中缝核神经元中IL-1受体的缺失将消除IL-1/ LPS对中枢SERT活性的影响。这一假设的验证将（1）为扩大研究细胞因子-5-HT相互作用提供关键数据，（2）有助于推进我们对调制的5-HT信号网络对疾病综合征范式中出现的抑郁样特征的贡献的理解。为达致这项建议的目的，我们计划进行以下研究：1.产生floxed IL-1 R小鼠; 2开发和表征肾上腺素能神经元特异性IL-1 R敲除小鼠。该项目的基本目标是实现IL-1 R的floxed等位基因的种系传递，在不存在Cre驱动程序的情况下对天然IL-1 R产生没有固有影响，并最终开发条件性IL-1 R敲除。总之，这些努力支持阐明促炎细胞因子调节脑功能和行为的体内机制的长期目标。 公共卫生关系：该项目调查了免疫挑战与控制神经递质血清素的关键基因之间的联系，以深入了解可能影响情绪障碍风险的机制，包括抑郁症，焦虑症和自闭症。该项目专门研究免疫介质白细胞介素-1及其受体在调节脑血清素转运蛋白（SERT），抗抑郁药物的主要目标。这些研究旨在开发一种新型的转基因小鼠模型，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。