Role of intestinal serotonin transporter in post traumatic stress disorder

肠道血清素转运蛋白在创伤后应激障碍中的作用

• 批准号: 10590033
• 负责人: Ravinder K Gill
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590033
• 关键词: Affect; Age; Aggressive behavior; Alleles; Amygdaloid structure; Animal Model; Anxiety; Anxiety Disorders; Bacteria; Behavior; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; CCL2 gene; CXCL1 gene; Cells; Chronic; Data; Desulfovibrio; Development; Disease Management; Disease model; Enteral; Epithelial Cells; Epithelium; Exhibits; FDA approved; Female; Fright; Functional disorder; Genes; Genetic Polymorphism; Genetic study; Health; Hippocampus; Hormones; Human Genetics; Impulsive Behavior; Individual; Intestines; Knock-in; Laboratories; Link; Measures; Medical; Mental Depression; Mental disorders; Microbe; Modeling; Molecular; Mood Disorders; Morbidity - disease rate; Mus; Neurons; Neurotransmitters; Occupational; Outcome Study; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Post-Traumatic Stress Disorders; Pre-Clinical Model; Predisposition; Regulatory Pathway; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Services; Sex Differences; Social isolation; Stress; Structure; Sulfate; Tissues; Transgenic Model; Trauma; Treatment outcome; Tryptophan 5-monooxygenase; Veterans; antimicrobial peptide; bench to bedside; conditioned fear; disability; disability payment; effective therapy; extracellular; fecal transplantation; gastrointestinal epithelium; gut bacteria; gut microbes; gut microbiota; gut-brain axis; ileum; insight; intestinal epithelium; liquid chromatography mass spectrometry; male; microbial; microbial based therapy; microbiota; microbiota-gut-brain axis; mind control; mouse model; neuroinflammation; novel; novel therapeutics; overexpression; resilience; response; reuptake; serotonin receptor; serotonin transporter; severe mental illness; sex; single-cell RNA sequencing; social; stress related disorder; stressor; suicidal behavior; sulfate reducing bacteria; transcriptome; traumatic stress

Post traumatic stress disorder (PTSD) a devastating psychiatric disorder and one of the most difficult service- related disabilities in Veterans, nonetheless without a consistently effective therapy. The only FDA-approved drugs for the treatment of PTSD are the selective serotonin reuptake inhibitors (SSRIs); the response rate to these drugs, however, is relatively small requiring development of more specific and individually effective therapies. In this regard, the neurotransmitter and hormone, serotonin (5-HT) is well-recognized for its role in depression, anxiety, aggression, impulsivity, and suicidal behaviors, which are frequently found in PTSD patients. Serotonin transporter, (SERT; SLC6A4), regulates the extracellular availability of 5-HT, and is a common target for SSRIs. Linkage of the short allele of the SERT gene polymorphism has been implicated in increasing the vulnerability to develop PTSD and predicting poor treatment outcome. In this regard, SERT is abundantly expressed in the gut and its dysfunction has been shown to cause gut microbiota alterations; albeit its role in the predisposition or progression of PTSD is not fully understood. To gain insights into the role of gut- microbiota and SERT interactions in PTSD, we utilized our recently developed novel transgenic model with inducible overexpression of SERT restricted to intestinal epithelial cells (SOEIEC) that exhibits low fecal 5-HT levels (LC/MS). The mouse model of protracted social isolation (SI), was used as chronic stressor important to elicit PTSD-like increased aggression in resident intruder assays. Interestingly, males with SOEIEC under SI exhibited increase in aggression while females were resilient as compared to wild type counterparts. To understand the sex-dependent differences, we correlated the aggression with structure of gut microbial communities. The data demonstrated a strong negative association of aggression with genus Desulfovibrio (sulfate reducing bacteria) and positive associations with Bacteroidales, Gastranaerophilales, and genus- Anaerotruncus. How 5-HT pools in the gut impact upstream factors affecting gut microbiota and triggers downstream factors in the gut and brain leading to PTSD like behavior in a sex-dependent manner is not known. Thus, our proposed studies will use cell specific SOE (in IEC and in neurons) to further elucidate PTSD related fear conditioning responses and aggression behavior and elucidate the underlying molecular mechanisms across gut-brain axis (Aim 1). Additional studies utilizing SOE and SERT KO are needed to assess the causal role of SERT induced gut-microbiota changes in predisposing mice (M/F) to fear deficits/increased aggression (Aim 2). This will be achieved by fecal microbial transplant and assessing the functional role of gut microbial changes by integrating the PTSD-like behavior with downstream targets (single cell RNA seq) and selected metabolites along gut-brain axis. The outcome of the studies will provide novel insights into the role of intestinal SERT in PTSD predisposition and will pave the way for microbial based therapeutics for PTSD management.

创伤后应激障碍（PTSD）一种毁灭性的精神疾病，是最困难的服务之一 尽管如此，退伍军人的相关障碍，但没有一贯的有效治疗。唯一的FDA批准 治疗PTSD的药物是选择性5-羟色胺再摄取抑制剂（SSRIS）；回应率 但是，这些药物相对较小，需要开发更具体和更个性化的 疗法。在这方面，神经递质和激素，5-羟色胺（5-HT）在其在 抑郁，焦虑，攻击性，冲动和自杀行为，经常在PTSD中发现 患者。 5-羟色胺转运蛋白（SERT； SLC6A4）调节5-HT的细胞外可用性，是一个 SSRI的常见目标。 Sert基因多态性的短等位基因的连锁已与 增加发展PTSD并预测不良治疗结果的脆弱性。在这方面，Sert是 在肠道中大量表达及其功能障碍已被证明会引起肠道菌群改变。虽然 它在PTSD的倾向或进展中的作用尚不完全了解。洞悉肠的作用 PTSD中的微生物群和Sert相互作用，我们利用了最近开发的新型转基因模型 SERT的诱导过表达仅限于肠上皮细胞（SOEIEC），该细胞表现出低粪便5-HT 水平（LC/MS）。长期的社会隔离（SI）的小鼠模型被用作慢性应激源对 引起类似PTSD的居民入侵者分析的攻击性。有趣的是，在SI领导下与Soeiec的男性 与野生型相比，女性的侵略性增加，而女性则具有弹性。到 了解性别依赖性差异，我们将侵略性与肠道微生物的结构相关联 社区。数据表明，侵略性与Desulfovibrio属有很强的负相关性。 （硫酸盐还原细菌）和与细菌的阳性关联，胃菌粒细胞和属 anaerotruncus。肠道中的5-HT池如何影响上游因素影响肠道菌群和触发因素 肠道和大脑的下游因素以性别依赖性方式导致PTSD类似于PTSD。 因此，我们提出的研究将使用细胞特异性SOE（在IEC和神经元中）进一步阐明PTSD相关 恐惧调节反应和侵略行为，并阐明了基本的分子机制 跨肠道轴（AIM 1）。需要使用SOE和SERT KO的其他研究来评估因果关系 Sert诱导的肠菌蛋白酶的作用在诱发小鼠（M/F）的恐惧/侵略性增加/增加的作用 （目标2）。这将通过粪便微生物移植和评估肠道微生物的功能作用来实现 通过将PTSD样行为与下游目标（单细胞RNA SEQ）集成并选择来改变并选择 沿肠道轴的代谢产物。研究的结果将为肠道作用提供新的见解 PTSD易感性的SERT将为基于微生物的PTSD管理铺平道路。