Phenotypic Changes Underlying Visceral Hypersensitivity in a Mouse Model of IBs

描述（由申请人提供）： 内脏疼痛目前是美国患者就诊的主要原因。在大多数胃肠道疾病中，疼痛通常是器官功能障碍的第一个警告;然而，在功能性肠病（FBD）中，如肠易激综合征（IBS），疼痛是病情的主要衰弱方面。我已经开发了一种新生儿结肠刺激（NCI）的小鼠模型，在没有组织病理学的情况下再现了IBS的主要特征-结肠超敏反应。我假设内脏感觉系统内的早期损伤导致结肠、外周神经和背根神经节水平的伤害性处理的长期改变。为了验证这一假设，我将采用三种不同的生理测定（梳理纤维制备，钙成像和完整的结肠感觉神经元的细胞内记录）沿着解剖分析，以确定NCI如何导致内脏高敏感性。通过了解这种模型中超敏反应的潜在机制，我将为我未来的研究计划奠定基础，研究内脏感觉神经元的变化如何导致和/或甚至可能导致FBD。迄今为止，我的训练已经导致了多篇关于感觉神经元可塑性的出版物，这些出版物在很大程度上依赖于解剖技术。然而，为了更全面地阐述神经元功能障碍在FBD中的作用，我需要获得必要的技能来进行内脏神经元的生理分析。匹兹堡大学目前的环境提供了一个很好的机会，获得这些技术技能，由于匹兹堡疼痛研究中心，胃肠病学部门的相关研究，以及基础科学和临床内脏疼痛研究人员之间的持续合作。专业技能发展也将得到学术职业发展办公室，匹兹堡大学神经科学中心和我的指导委员会的支持，该委员会由从事内脏疼痛各个方面工作的翻译科学家组成。通过进一步发展我的技术和职业生涯，我将完成我的过渡到一个独立的学术研究。相关性：大约15%的公众患有肠易激综合征（IBS），其定义特征是顽固性慢性疼痛。这项拟议的研究使用IBS小鼠模型来确定这种慢性疼痛的来源和机制，以便未来的实验能够设计出能够提供显着缓解的新疗法。

DESCRIPTION (provided by applicant): Visceral pain is currently the leading cause for patient visits in the U.S. In most gastrointestinal diseases, pain is often the first warning of organ dysfunction; however, in functional bowel disorders (FBD), like irritable bowel syndrome (IBS), pain is the main debilitating aspect of the condition. I have developed a mouse model of neonatal colon irritation (NCI) that reproduces the principal characteristic of IBS - colon hypersensitivity in the absence of histopathology. I hypothesize that early insult within the viscerosensory system results in long-lasting alterations in nociceptive processing at the level of the colon, peripheral nerve and DRG. To test this hypothesis I will employ three different physiological assays (a teased fiber preparation, calcium imaging and intracellular recordings from intact colon sensory neurons) along with anatomical analysis to determine how NCI results in visceral hypersensitivity. By understanding the underlying mechanisms of hypersensitivity in this model, I will lay the foundation for my future research program to study how changes in visceral sensory neurons contribute to, and/or may even cause, FBD. My training to date has resulted in multiple publications on sensory neuron plasticity that have relied heavily on anatomical techniques. However, to more fully address the role of neuronal dysfunction in FBD, I need to obtain the skills necessary to conduct physiological analysis of visceral neurons. The current environment at the University of Pittsburgh provides an excellent opportunity to obtain these technical skills due to the Pittsburgh Center for Pain Research, the associated research in the Division of Gastroenterology, and ongoing collaborations between basic science and clinical visceral pain investigators. Professional skills development will also be supported by the Office of Academic Career Development, the Center for Neuroscience at the University of Pittsburgh and my Mentoring Committee consisting of translational scientists working on various aspects of visceral pain. By furthering my technical and professional career development I will complete my transition into an independent academic researcher. Relevance: Approximately 15% of the general public suffers from Irritable Bowel Syndrome (IBS), of which the defining characteristic is intractable chronic pain. The proposed study uses a mouse model of IBS to identify the source and mechanism(s) of this chronic pain so that future experiments will be able to design novel therapies that will provide significant relief.