Phenotypic Changes Underlying Visceral Hypersensitivity in a Mouse Model of IBs

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，如易激惹 肠综合征（IBS），疼痛是主要的衰弱方面的条件。我开发了一个小鼠模型 新生儿结肠刺激（NCI），再现IBS的主要特征-结肠超敏反应， 缺乏组织病理学检查。我假设内脏感觉系统的早期损伤导致 在结肠、外周神经和DRG水平的伤害性处理中的持久改变。测试 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 和来自完整结肠感觉神经元的细胞内记录）沿着解剖学分析以确定 NCI如何导致内脏高敏感性通过了解超敏反应的潜在机制 在这个模型中，我将为我未来的研究计划奠定基础，研究内脏的变化， 感觉神经元有助于和/或甚至可能导致FBD。迄今为止，我的训练导致了多个 在很大程度上依赖于解剖技术的感觉神经元可塑性的出版物。但要 为了更全面地解决神经元功能障碍在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 一个极好的机会，以获得这些技术技能，由于匹兹堡疼痛研究中心， 胃肠病学部门的相关研究，以及基础科学之间正在进行的合作 和临床内脏疼痛研究者。专业技能发展也将得到人力厅的支持。 学术职业发展，匹兹堡大学神经科学中心和我的 指导委员会由致力于内脏疼痛各个方面的翻译科学家组成。通过 为了促进我的技术和职业发展，我将完成我的过渡， 独立学术研究员。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。拟议 研究使用IBS小鼠模型来确定这种慢性疼痛的来源和机制，以便将来 实验将能够设计新的疗法，将提供显着的缓解。

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.