Evaluation of sensory neuron plasticity following neonatal maternal separation

新生儿母体分离后感觉神经元可塑性评价

• 批准号: 7875043
• 负责人: Julie A Carlsten Christianson
• 金额: $ 0.85万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7875043
• 关键词: Address; Adult; Adverse event; Affect; Afferent Neurons; Animals; Ankyrins; Behavioral; Biological Assay; Calcium; Caring; Cells; Characteristics; Chemicals; Childhood; Colitis; Colon; Colorectal; Development; Disease; Distal; Epithelial; Evaluation; Event; Future; Genus Cola; Gestational Age; Goals; Growth Factor; Histopathology; Hyperalgesia; Hypersensitivity; Image; Incidence; Individual; Infant; Inflammation; Inflammatory; Injury; Intervention; Intestines; Investigation; Irritable Bowel Syndrome; Label; Life; Measures; Mechanics; Membrane; Mentored Research Scientist Development Award; Modeling; Molecular; Mus; Neonatal; Neonatal Intensive Care Units; Neurons; Nociception; Organ; Outcome; Pain; Parents; Pathway interactions; Patients; Perception; Peripheral; Peripheral Nerves; Permeability; Peroxidases; Physiological; Predisposition; Premature Infant; Process; Production; Rattus; Research; Reverse Transcriptase Polymerase Chain Reaction; Sensory; Sexual abuse; Spinal Ganglia; Stress; Sulfonic Acids; Survival Rate; Symptoms; System; Testing; Therapeutic Intervention; Trinitrobenzenes; Visceral; Visceral pain; Visit; Work; base; cell motility; colorectal distension; critical period; design; experience; improved; irritation; maternal separation; mouse model; nerve supply; novel; protein expression; public health relevance; receptor; research study; response; therapeutic target; vanilloid receptor subtype 1

DESCRIPTION (provided by applicant): Visceral pain is currently the leading cause for patient visits in the U.S and is the main debilitating aspect in irritable bowel syndrome (IBS). The incidence of IBS is higher among individuals who experienced adverse events during childhood, including verbal, physical and sexual abuse, as well as disease of later affected organs. The focus of the parent K01 proposal was a novel mouse model of neonatal colon irritation (NCI) that reproduced the principal characteristic of IBS - colon hypersensitivity in the absence of histopathology. The main hypothesis was that early insult in the viscerosensory system produces a long-lasting alteration in nociceptive processing at the level of the colon, peripheral nerve and DRG. The current proposal aims to broaden the focus of the original K01 award, by adding a model of neonatal stress (neonatal maternal separation [NMS]) to the ongoing studies of NCI in an attempt to gain a more complete understanding of the vulnerabilities of the developing viscerosensory system and the long-lasting deleterious effects that can result from perturbations during the neonatal critical period. The experiments in this application are outlined in two specific aims and are designed to functionally test the hypothesis that NMS produces lifelong visceral hypersensitivity in mice through heightened excitability of peripheral sensory neurons due to changes in expression of specific membrane receptors, which exacerbate the response to experimental colitis. SA1: To test the hypothesis that NMS in mice produces long-lasting colon hypersensitivity and increased excitability/receptor changes in peripheral nerves innervating the distal colon. To test this hypothesis, a) the visceromotor response (VMR) to colorectal distension will be evaluated in adult NMS mice and b) single cell RT-PCR and calcium imaging will be performed on colon DRG neurons to determine changes in expression, function and interactions between TRPV1 and TRPA1, two channels proposed to regulate visceral sensitivity. SA2: To test the hypothesis that NMS enhances susceptibility to experimental colitis and exacerbates inflammation-induced changes in the distal colon and associated peripheral sensory neurons. To test this hypothesis, trinitrobenzene sulfonic acid (TNBS) will be administered to induce colitis and a) the extent of inflammation will be determined by assessing increases in myeloperoxidase (MPO) activity and growth factor production, and b) VMR, single cell RT-PCR and calcium imaging will be repeated to determine how colitis affects the already altered nociceptive processing in the NMS mice. The addition of the NMS model to ongoing studies of NCI allows for comparisons to be made between two different models of neonatal insult with the same behavioral outcome, heightened visceral sensitivity. Discoveries made using these models will allow for the identification of common and/or divergent pathways that underlie visceral hypersensitivity, which could serve as potential therapeutic targets for treatment of IBS and other functional bowel disorders. PUBLIC HEALTH RELEVANCE: The focus of my research is on how adverse events during neonatal development can permanently alter pain processing in adulthood. As neonatal care improves, early gestational-age infant survival rates are increasing. However, these premature infants can spend weeks or months in the neonatal care unit where they are subjected to adverse conditions, both in terms of stress from maternal separation and from the multiple painful interventions required on a daily basis. The experiments included in this proposal will address neonatal stress- related outcomes in visceral pain processing, in terms of colon sensitivity, the expression of pain-related molecules on neurons innervating the colon and susceptibility to future colon insult (inflammation).

描述(申请人提供)：内脏疼痛目前是美国患者就诊的主要原因，也是肠易激综合征(IBS)的主要衰弱因素。IBS的发病率在童年经历过不良事件的人中较高，包括言语、身体和性虐待，以及后来受到影响的器官疾病。母公司K01提案的重点是一种新的新生儿结肠刺激(NCI)小鼠模型，该模型在没有组织病理学的情况下再现了IBS-结肠超敏的主要特征。主要的假设是，内脏感觉系统的早期伤害会在结肠、外周神经和背根节水平上产生长期的伤害性处理改变。目前的建议旨在扩大最初的K01奖项的重点，在NCI正在进行的研究中增加一个新生儿应激模型(新生儿母体分离[NMS])，试图更全面地了解发展中的内脏感觉系统的脆弱性，以及新生儿关键期期间的扰动可能导致的长期有害影响。本应用中的实验概述了两个特定的目标，旨在从功能上测试NMS通过改变特定膜受体的表达而增强外周感觉神经元的兴奋性，从而加剧对实验性结肠炎的反应，从而在小鼠中产生终生内脏高敏感性的假设。SA1：为了验证NMS在小鼠中产生持久的结肠超敏反应，并增加支配远端结肠的外周神经的兴奋性/受体变化的假设。为了验证这一假说，a)将评估成年NMS小鼠对结直肠扩张的内脏运动反应(VMR)，b)将对结肠背根神经节神经元进行单细胞RT-PCR和钙成像，以确定TRPV1和TRPA1之间的表达、功能和相互作用，这两个通道被认为是调节内脏敏感性的两个通道。SA2：为了验证NMS增加实验性结肠炎的易感性并加剧炎症诱导的远端结肠和相关外周感觉神经元变化的假设。为了验证这一假说，将使用三硝基苯磺酸(TNBS)诱导结肠炎，并且a)通过评估髓过氧化物酶(MPO)活性和生长因子产生的增加来确定炎症的程度，以及b)将重复VMR、单细胞RT-PCR和钙成像来确定结肠炎如何影响NMS小鼠已经改变的伤害感受处理。将NMS模型添加到正在进行的NCI研究中，可以在两种不同的新生儿侮辱模型之间进行比较，这些新生儿侮辱具有相同的行为结果，即增强内脏敏感性。利用这些模型所做的发现将有助于确定内脏高敏感性的共同和/或不同途径，这可能成为治疗IBS和其他功能性肠道疾病的潜在治疗靶点。 公共卫生相关性：我的研究重点是新生儿发育过程中的不良事件如何永久性地改变成年后的疼痛处理。随着新生儿护理的改善，早期妊娠婴儿的存活率正在上升。然而，这些早产儿可能会在新生儿护理病房呆上几周或几个月，在那里他们面临着来自母亲分离和每天所需的多次痛苦干预的压力。这项提议中包括的实验将研究内脏疼痛处理中与新生儿应激相关的结果，如结肠敏感性、支配结肠的神经元上疼痛相关分子的表达以及未来结肠损伤(炎症)的易感性。