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

基本信息

批准号：
10452753
负责人：
Katelyn Sadler
金额：
$ 11.51万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452753
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 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 Injections Injury Intestines Laboratory Research Measures Mediating Mental Depression Mentors Modeling Mus Nerve Neuraxis Neurobiology Neurons Neurotransmitters Nociception Nucleus solitarius Operative Surgical Procedures Opioid Output Pain Pain intensity Pain management Pathology Patients Penicillins Peripheral 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 Wild Type Mouse Wisconsin Work affective disturbance afferent nerve base cell type 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

项目摘要

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.

研究总结疼痛是镰状细胞病 (SCD) 患者最常见的并发症。 SCD 患者患有与血管闭塞发作相关的剧烈急性疼痛和通常无症状的慢性疼痛明显的病理。阿片类药物是治疗 SCD 疼痛的主要疗法，尽管其长期副作用影响、缺乏疗效以及相关的治疗障碍。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制了解。很少有研究表明描述了大脑在 SCD 疼痛中的作用，尽管患者报告有中枢敏化和情感共同作用发病率，这两者都与 SCD 疼痛强度和频率增加相关。中央核杏仁核 (CeA) 是由急性疼痛、慢性疼痛和情感障碍激活的边缘脑区域；在转基因 SCD 小鼠中注意到 CeA 活性增加。我们的长期目标是确定 SCD 相关因素增加 CeA 神经元活动和疼痛样行为，以开发新型 SCD 疼痛疗法。这该提案将研究肠道微生物组如何影响 SCD 中的 CeA 活性。来自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 模型与健康对照模型不同（即表现出生态失调）。抗或益生菌操作肠道微生物组改变了 SCD 小鼠的疼痛样行为和 CeA 信号传导。本次活动的具体目标该提案将检查这些变化背后的神经机制。在具体目标 1 中，我们将使用纤维光度测定法测量以下条件下的背景和疼痛诱发的 CeA 活性：(A) 伪- 用 SCD 粪便材料重新定植的无菌小鼠，(B) 接受纵向青霉素治疗的 SCD 小鼠， (C) 接受迷走神经切断手术的 SCD 小鼠。这些实验将使我们能够确定程度以及 SCD 肠道菌群失调影响 CeA 活性的机制。在具体目标 2 中，我们将直接操纵选定的 CeA 神经元群体，以确定每个神经元如何参与与菌群失调相关的疼痛。我们将首先使用光遗传学抑制重新定植 SCD 的假无菌小鼠中选定的 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 生态失调相关疼痛。最后，我们将确定 SCD 肠道微生物组可以通过哪些新的神经元信号传导途径造成疼痛。这些实验将成为我的独立研究实验室的基础，该实验室将研究伤害感受的解剖学和化学基础，以便开发个性化治疗方法患有 SCD 和其他慢性疼痛疾病的个体。