Phenotypic Changes Underlying Visceral Hypersensitivity in a Mouse Model of IBs

IB 小鼠模型内脏过敏的表型变化

• 批准号: 7750619
• 负责人: Julie A Carlsten Christianson
• 金额: $ 13.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7750619
• 关键词: Address; Adult; Affect; Afferent Neurons; Basic Science; Biological Assay; Biopsy; Calcium; Characteristics; Chemicals; Clinical; Collaborations; Colon; Development; Disease; Distal; Electrodes; Environment; Fiber; Foundations; Functional disorder; Future; Gastroenterology; Gastrointestinal Diseases; General Population; Genus Cola; Growth Factor; Habits; Histopathology; Hypersensitivity; Image; Immunohistochemistry; In Vitro; Inflammation; Intestines; Irritable Bowel Syndrome; Label; Mechanics; Mentors; Modeling; Mus; Neonatal; Nerve; Neuronal Dysfunction; Neurons; Neurosciences; Nociception; Organ; Outcome; Pain; Pain Research; Patients; Pelvis; Peripheral; Peripheral Nerves; Phenotype; Physiological; Population; Postdoctoral Fellow; Preparation; Prevalence; Process; Protein Analysis; Publications; Rattus; Research; Research Personnel; Role; Scientist; Sensory; Site; Source; Spinal; Spinal Cord; Splanchnic Nerves; Stimulus; System; Techniques; Testing; Training; Universities; Visceral; Visceral Afferents; Visceral pain; Visit; Work; career development; cell motility; chronic pain; colon distension; density; design; irritation; mouse model; nerve supply; neurochemistry; novel; programs; rectal; research study; response; skills

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.

描述（由申请人提供）： 内脏疼痛是目前在大多数胃肠道疾病中在美国访问患者的主要原因，疼痛通常是器官功能障碍的第一个警告。但是，在功能性肠病（FBD）中，像肠易激综合征（IBS）一样，疼痛是该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，该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。我假设内脏感体系内的早期侮辱会导致在结肠，周围神经和DRG水平上的伤害感受器的持久变化。为了检验该假设，我将采用三种不同的生理测定方法（纤维制剂，钙成像和完整结肠感觉神经元的细胞内记录）以及解剖学分析，以确定NCI如何导致内脏超敏反应。通过了解该模型中超敏反应的潜在机制，我将为未来的研究计划奠定基础，以研究内脏感觉神经元的变化如何促进和/或甚至可能引起FBD。迄今为止，我的培训导致了多个有关感官神经元可塑性的出版物，这些出版物严重依赖解剖技术。但是，为了更充分地解决神经元功能障碍在FBD中的作用，我需要获得对内脏神经元进行生理分析所需的技能。匹兹堡大学的当前环境为匹兹堡疼痛研究中心，胃肠病学部的相关研究以及基础科学与基础科学与临床内脏疼痛研究人员之间的持续合作提供了一个绝佳的机会来获得这些技术技能。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以及我的指导委员会的支持，包括转化科学家从事内脏疼痛的各个方面。通过进一步发展我的技术和职业发展，我将完成我向独立的学术研究员的过渡。相关性：大约15％的公众患有肠易激综合征（IBS），其中定义特征是棘手的慢性疼痛。拟议的研究使用IBS的小鼠模型来识别这种慢性疼痛的来源和机制，从而使未来的实验能够设计出可提供明显缓解的新型疗法。