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

• 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
• 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

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.

项目概要 妊娠期间接触酒精可能导致一系列轻度到重度残疾，包括 认知和行为缺陷代表一个连续体，称为胎儿酒精谱系障碍 (FASD)，在美国一些地区的患病率约为 4.8%。越来越多的证据强烈表明 中枢神经系统 (CNS) 发育过程中酒精暴露对细胞和 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、促炎细胞因子白介素-1β (IL-1β) 的表达， 肿瘤坏死因子-α (TNF-α) 和趋化因子 CCL2 显着升高。虽然有证据表明 FASD 儿童中观察到的感觉异常（包括触觉敏感度）被认为是以下原因造成的： 心理社会因素，根本原因可能包括神经功能障碍。事实上，动物模型 PAE 揭示了对光触的高度敏感性，这是一种众所周知的病理性感觉状况，由 脊髓中神经元的异常活动。临床上，触摸超敏反应被称为慢性疼痛异常。 疼痛患者和异常性疼痛动物模型显示脊髓中发生疼痛神经元的病理激活 脊髓由 IL-1β、TNF-α 和 CCL2 介导。胶质细胞（星形胶质细胞和小胶质细胞）是这些细胞的主要产生者 促炎细胞因子。因此，异常性疼痛和 PAE 的动物模型揭示了令人惊讶的神经免疫 重叠。对动物异常性疼痛的研究表明，外周白细胞响应于 覆铜板2。值得注意的是，白细胞通过脊髓微血管内皮细胞（MEC）进入中枢神经系统 β2-粘附分子、淋巴细胞功能相关抗原 1 (LFA-1)，以及重要的神经胶质细胞控制 MEC 的健康屏障功能。奇怪的是，有证据表明 PAE 会导致结构异常 神经胶质 CNS-MEC 接口。因此，长期目标是确定脊髓 MEC 和神经免疫适应 PAE 的雄性和雌性后代会增强成年后对神经病的易感性。新的治疗靶点 可以确定缓解异常的神经免疫功能。总体目标将确定 PAE 的影响 影响男性脊髓免疫适应对小周围神经和免疫挑战的反应 女性。总体假设：PAE 增强脊髓和外周促炎免疫 伤害性通路中的反应使轻微的伤害或对慢性神经病的易感性 挑战。该提案的目标是： (I) 检查 PAE 对细胞因子谱和功能的影响 介导成人轻微损伤和免疫挑战引起的神经病变，（II）确定功能 PAE 引起的血脊髓屏障紧密连接缺陷对神经病变的影响，以及 (III) 确定 PAE 引起的周围免疫反应缺陷，从而导致对神经病变的易感性。 结果将为理解异常 PNS 和 CNS 的发育起源提供新知识 PAE 引起的免疫相互作用，揭示了对成人发病疾病（如神经性疼痛）的易感性。