Sickle cell disease gut dysbiosis effects on CNS pain processing

镰状细胞病肠道菌群失调对中枢神经系统疼痛处理的影响

• 批准号: 10747045
• 负责人: Katelyn Sadler
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747045
• 关键词: Acute Pain; Adult; Advisory Committees; Affect; Affective; Agonist; Amygdaloid structure; Anatomy; Antibiotics; Anxiety; Automobile Driving; Award; Behavior; Behavioral; Brain; Brain imaging; Brain region; Cell Nucleus; Cells; Central Nervous System; Chemicals; Childhood; Complication; Data; Disease; Disease model; Exhibits; Fiber; Foundations; Frequencies; Fright; G-Protein-Coupled Receptors; Gene Expression Profile; Germ-Free; Goals; HTR2A gene; Hypoxia; Individual; Inflammatory; Injections; Injury; Intestines; Laboratory Research; Learning; Measures; Mediating; Mental Depression; Mentors; Modeling; Mus; Nerve; Neurobiology; Neurons; Neuropathy; Neurotransmitters; Nociception; Nucleus solitarius; Operative Surgical Procedures; Opioid; Output; Pain; Pain intensity; Pain management; Pathology; Patients; Penicillins; Peripheral Nervous System; Phase; Photometry; Population; Probiotics; Process; Proxy; Publishing; Reporting; Research; Research Personnel; Role; Sensory; Serotonin; Serotonin Production; Serotonin Receptor 5-HT2A; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Site; Social Interaction; Source; Spinal; Structure; Testing; Time; Training; Transgenic Organisms; Vagotomy; Variant; Veno-Occlusive Disease; Vertebral column; Visceral; Wild Type Mouse; Wisconsin; Work; affective disturbance; afferent nerve; cell type; central pain; central sensitization; chronic pain; chronic painful condition; comorbidity; depressive symptoms; dysbiosis; experimental study; gut bacteria; gut dysbiosis; gut microbes; gut microbiome; job market; medical schools; microbial; microbiome; microbiome research; mouse model; neuronal circuitry; neurotransmission; non-opioid analgesic; novel; optogenetics; pain processing; parabrachial nucleus; personalized therapeutic; pre-clinical; prophylactic; receptor; side effect; symptom treatment; tenure track

Research Summary Pain is the most common complication for patients with sickle cell disease (SCD). Patients with SCD suffer from intense acute pain that is associated with vaso-occlusive episodes and chronic pain which frequently has no obvious pathology. Opioids are the main therapy used to treat SCD pain, despite their negative long-term side effects, lack of efficacy, and associated treatment barriers. In order to develop better therapies for SCD pain, a more mechanistic understanding of the neurobiological basis of SCD pain is needed. Very few studies have characterized the role of the brain in SCD pain, despite patient reports of central sensitization and affective co- morbidities, both of which are correlated with increased SCD pain intensity and frequency. The central nucleus of the amygdala (CeA) is a limbic brain region activated by acute pain, chronic pain, and affective disturbances; increased CeA activity is noted in transgenic SCD mice. Our long-term goal is to identify SCD-related factors that increase CeA neuronal activity and pain-like behaviors in order to develop novel SCD pain therapies. This proposal will examine how the gut microbiome influences CeA activity in SCD. Data from germ-free mice show that an intact gut microbiome is critical for normal amygdala function. The gut microbiome of patients and mouse models with SCD differs from that of healthy controls (i.e. exhibit dysbiosis). Anti- or probiotic manipulation of the gut microbiome changes pain-like behaviors and CeA signaling in SCD mice. The specific aims of this proposal will examine the neuronal mechanisms underlying these changes. In Specific Aim 1, we will use fiber photometry to measure background and pain-evoked CeA activity in the following conditions: (A) pseudo- germfree mice recolonized with SCD fecal material, (B) SCD mice that received longitudinal penicillin treatment, and (C) SCD mice that underwent vagotomy surgery. These experiments will allow us to determine the extent and mechanism through which SCD gut dysbiosis affects CeA activity. In Specific Aim 2, we will directly manipulate select populations of CeA neurons to determine how each is involved in dysbiosis-related pain. We will first use optogenetics to inhibit activity of select CeA neurons in pseudo-germfree mice recolonized with SCD fecal material. We will then determine if 5HT2A receptor activity in the CeA contributes to SCD dysbiosis-related pain. Finally, we will identify novel neuronal signaling pathways through which the SCD gut microbiome could be driving pain. These experiments will be the foundation for my independent research laboratory which will study the anatomical and chemical basis of nociception in order to develop personalized therapeutics for individuals suffering from SCD and other chronic pain disorders.

研究摘要 疼痛是镰状细胞疾病（SCD）患者最常见的并发症。 SCD患者患有 与血管结合发作和慢性疼痛相关的强烈急性疼痛经常没有 明显的病理。阿片类药物是用于治疗SCD疼痛的主要疗法，尽管长期负面 影响，缺乏疗效和相关的治疗障碍。为了开发更好的SCD疼痛疗法， 需要对SCD疼痛的神经生物学基础有更多的机械理解。很少有研究 尽管患者报道了中枢敏化和情感共同的，但仍表征了大脑在SCD疼痛中的作用 病态性，两者都与SCD疼痛强度和频率增加相关。中央核 杏仁核（CEA）是一个边缘大脑区域，该区域是由急性疼痛，慢性疼痛和情感障碍激活的。 转基因SCD小鼠的CEA活性增加。我们的长期目标是确定与SCD相关的因素 这会增加CEA神经元活性和类似疼痛的行为，以开发新的SCD疼痛疗法。这 提案将研究肠道微生物组如何影响SCD中的CEA活性。无菌小鼠的数据显示 完整的肠道微生物组对于正常的杏仁核功能至关重要。患者和小鼠的肠道微生物组 SCD的模型与健康对照的模型不同（即表现出营养不良）。抗益生菌操纵 肠道微生物组改变了SCD小鼠的疼痛样行为和CEA信号传导。这个特定的目的 提案将检查这些变化的神经元机制。在特定目标1中，我们将使用纤维 在以下条件下测量背景和疼痛诱发的CEA活性的光度法：（a）伪 用SCD粪便材料重新定殖的无毛小鼠，（b）接受纵向青霉素治疗的SCD小鼠， （c）接受迷走术手术的SCD小鼠。这些实验将使我们能够确定 SCD肠道营养不良会影响CEA活性的机制。在特定的目标2中，我们将直接 操纵CEA神经元的精选种群，以确定每个人如何参与与营养不良相关的疼痛。我们 将首先使用光遗传学来抑制用SCD重新殖的伪无菌小鼠中精选的CEA神经元的活性 粪便材料。然后，我们将确定CEA中的5HT2A受体活性是否有助于SCD营养不良相关 疼痛。最后，我们将确定新型的神经元信号通路，SCD肠道微生物组可以通过 驱动疼痛。这些实验将是我的独立研究实验室的基础 研究伤害感受的解剖学和化学基础，以开发个性化的治疗剂 患有SCD和其他慢性疼痛障碍的人。