Prenatal Alcohol Exposure Potentiates Pain via Lifelong Spinal-immune Changes

产前酒精暴露会通过终生脊髓免疫变化加剧疼痛

基本信息

批准号：
10224027
负责人：
ERIN Damita MILLIGAN
金额：
$ 28.42万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224027
关键词：
Adhesions Adult Afferent Neurons Age-Years Anatomy Animal Model Animals Astrocytes Behavior Behavioral Blood Brain CCL2 gene CXC Chemokines Cell Adhesion Molecules Cell physiology Cells Child Chronic Clinical Cognitive Data Defect Development Disease susceptibility Dorsal Endothelial Cells Ethanol Etiology Exposure to Female Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fetus Goals HIV 1 Envelope Protein gp120 Hypersensitivity Immune Immune response Immune signaling Immune system Infant Inflammation Inflammatory Injury Interleukin-1 beta Knowledge Lead Leukocyte Trafficking Leukocytes Light Lymphocyte Function-Associated Antigen-1 Macaca mulatta Mediating Messenger RNA Microglia Microscopy Minor Molecular Myeloid Cells Nervous System Physiology Neuraxis Neuroglia Neuroimmune Neurologic Dysfunctions Neurons Neuropathy Neurotransmitters Nociception Onset of illness Outcome Pain Pathologic Pathway interactions Patients Peripheral Peripheral Nerves Peripheral Nervous System Diseases Physiological Adaptation Predisposition Pregnancy Prevalence Proteins Psychosocial Factor Public Health Rattus Reporting Resolution Risk Rodent Model Role Saccharin Sciatic Neuropathy Sensory Sex Differences Signal Transduction Signaling Molecule Site Spinal Spinal Cord Spine pain Structural defect T-Lymphocyte TNF gene Tactile Tight Junctions Touch sensation alcohol exposure allodynia chemokine chronic neuropathic pain chronic pain patient cytokine disability macrophage male migration monocyte nervous system development new therapeutic target nociceptive response offspring pain signal painful neuropathy peripheral nerve damage prenatal programs response sciatic nerve trafficking transmission process

项目摘要

PROJECT SUMMARY Exposure to alcohol during gestation can lead to a constellation of mild to severe disabilities that includes cognitive and behavioral deficits representing a continuum referred to as Fetal Alcohol Spectrum Disorders (FASD), with a prevalence of ~4.8% in some US regions. A growing body of evidence strongly implicates the adverse impact of alcohol exposure during central nervous system (CNS) development on cellular and molecular programing of neuroimmune function. In animal models of prenatal alcohol exposure (PAE), expression of the brain's immune signaling molecules, the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and the chemokine CCL2, are significantly elevated. While evidence of sensory abnormalities including tactile sensitivity observed in children with FASD are thought to be a result of psychosocial factors, the underlying cause may include neurological dysfunction. Indeed, animal models of PAE reveal heightened sensitivity to light touch, a well-known pathological sensory condition mediated by aberrant neuronal actions in the spinal cord. Clinically, touch hypersensitivity is known as allodynia in chronic pain patients, and animal models of allodynia show pathological activation of pain neurons occurs in the spinal cord mediated by IL-1β, TNF-α and CCL2. Glial cells (astrocytes & microglia) are key producers of these proinflammatory cytokines. Thus, animal models of allodynia and PAE reveal a surprising neuroimmune overlap. Studies of allodynia in animals show peripheral leukocytes traffic to the spinal cord in response to CCL2. Notably, leukocytes cross spinal microvascular endothelial cells (MECs) into the CNS by the action of the β2-adhesion molecule, lymphocyte function associated antigen 1 (LFA-1), and importantly, glial cells control the healthy barrier function of MECs. Curiously, evidence shows PAE causes structural abnormalities at the glial CNS-MEC interface. Thus, the long-term goal is to identify spinal MEC & neuroimmune adaptations in PAE male and female offspring that enhance adult susceptibility to neuropathy. New therapeutic targets to alleviate aberrant neuroimmune function may be identified. The overall objective will identify the impact PAE exerts on responses of spinal immune adaptations to minor peripheral nerve & immune challenge in males & females. Overarching Hypothesis: PAE potentiates spinal and peripheral proinflammatory immune responses in the nociceptive pathway creating susceptibility for chronic neuropathy from minor insult or challenge. The Aims of the proposal will: (I) Examine the impact of PAE on cytokine profile and function in mediating neuropathy from minor insults and immune challenges in adults, (II) Determine the functional consequences of PAE-induced tight junction defects of the blood-spinal barrier on neuropathy, and (III) Determine PAE-induced defects of the peripheral immune response underlying susceptibility to neuropathy. Results will provide new knowledge for understanding the developmental origins of aberrant PNS- and CNS- immune interactions due to PAE, revealing susceptibilities to adult onset diseases such as neuropathic pain.

项目摘要妊娠期间暴露于酒精会导致一系列轻度至重度疾病，包括认知和行为定义代表称为胎儿酒精谱系障碍的连续性（FASD），一些美国地区的患病率约为4.8％。越来越多的证据强烈暗示中枢神经系统（CNS）发育期间酒精暴露在细胞和神经免疫功能的分子编程。在产前酒精暴露（PAE）的动物模型中，大脑免疫信号分子的表达，促炎细胞因子白介素1β（IL-1β），肿瘤坏死因子-Alpha（TNF-α）和趋化因子CCL2显着升高。同时证据感觉异常包括在FASD儿童中观察到的触觉灵敏度，被认为是心理因素，根本原因可能包括神经功能障碍。确实，动物模型 PAE揭示了对轻触摸的敏感性，这是一种众所周知的病理感觉状况脊髓中异常的神经元作用。在临床上，触摸超敏反应被称为慢性异常疼痛患者和异源性动物模型显示疼痛神经元的病理激活发生在脊柱中由IL-1β，TNF-α和CCL2介导的脐带。神经胶质细胞（星形胶质细胞和小胶质细胞）是其中的关键生产国促炎细胞因子。那样，异常动物和PAE的动物模型揭示了一个惊喜的神经免疫重叠。动物中异常性疾病的研究表明，外周白细胞流动到脊髓 CCL2。值得注意的是，白细胞通过脊柱微血管内皮细胞（MEC）通过作用 β2粘附分子，淋巴细胞功能相关的抗原1（LFA-1），重要的是，神经胶质细胞控制 MEC的健康屏障功能。奇怪的是，有证据表明PAE在 Glial CNS-MEC接口。这是长期目标是确定脊柱MEC和神经免疫性适应 PAE男性和女性后代增强了成人对神经病的敏感性。新的治疗靶点可以鉴定出缓解异常神经免疫功能。总体目标将确定影响PAE的影响对男性的脊柱免疫适应对轻微神经和免疫挑战的脊柱免疫适应反应女性。总体假设：PAE增强脊柱和周围促炎性免疫伤害感受途径中的反应使因轻伤或挑战。该提案的目的将：（i）检查PAE对细胞因子概况和功能的影响介导成人轻伤和免疫挑战的神经病，（ii）确定功能 PAE诱导的神经病血液屏障的紧密连接缺陷和（iii）的后果确定PAE诱导的外周免疫响应对神经病的敏感性的缺陷。结果将为理解异常PNS和CNS-的发展起源提供新知识由于PAE引起的免疫相互作用，揭示了对成年发作疾病（例如神经性疼痛）的敏感性。