Colon afferents: molecular identity, histology/morphology and hypersensitivity

结肠传入：分子身份、组织学/形态学和超敏反应

• 批准号: 8764385
• 负责人: Bin Feng
• 金额: $ 11.12万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764385
• 关键词: Address; Adverse effects; Affect; Anatomy; Area; Basic Science; Behavioral; Brain; Cells; Characteristics; Chemicals; Chronic; Classification; Clinic; Colectomy; Colon; Colorectal; Computer Simulation; Constipation; Data; Development; Disease; Distal; Dyes; Electric Stimulation; Electrodes; Electrophysiology (science); Elements; Environment; Evaluation; Exhibits; Fiber; Gastroenterologist; Gene Expression Profile; Generations; Goals; Health Care Costs; Histologic; Histology; Hodgkin Disease; Human; Hypersensitivity; In Vitro; Individual; Intestinal Mucosa; Intestines; Intracolonic; Ion Channel; Irritable Bowel Syndrome; Label; Location; Lumbar nerve; Malignant Neoplasms; Mechanical Stress; Mechanics; Membrane Potentials; Modeling; Molecular; Molecular Target; Morphology; Mus; Nerve; Neurobiology; Neurons; Organ; Outcome; Pain; Pathway interactions; Patients; Pelvis; Peripheral; Physiological; Population; Preparation; Quality of life; Research; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Sensory; Specificity; Spinal Cord; Spinal Ganglia; Splanchnic Nerves; Stretching; Sulfonic Acids; Symptoms; Techniques; Time; Translations; Trinitrobenzenes; Visceral; Visceral pain; Visit; Work; Zymosan; improved; in vivo; innovation; nerve supply; neurobiotin; neurochemistry; neuronal cell body; novel; public health relevance; receptor; rectal; relating to nervous system; research study; response; simulation

DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is estimated to affect up to 15% of the population in the USA, with negative effects on quality of life and annual direct and indirect health care costs of ~30 billion U.S. dollars. Pain is the characteristic symptom of IBS and the main reason for patient visits to gastroenterologists. Accumulating evidence suggests that heightened peripheral sensory input from colorectal afferents (i.e., afferent sensitization) is necessary for the persistence of IBS-related pain and hypersensitivity. The goal of the proposed research is to investigate molecular/neurochemical identities ('chemotype') and histological locations of functionally distinct afferent classes in the colorectum, from which information about mechanisms of afferent sensitization that contribute to colorectal hypersensitivity will be revealed. Specifically, a novel ex vivo preparation of the mouse colorectum with nerves and spinal cord in continuity will be used to couple functional study of afferent electrophysiology with chemotype evaluation and afferent ending anatomy. Studies will be done in the context of long-term models of visceral hypersensitivity induced by intracolonic treatment with zymosan or trinitrobenzene sulfonic acid (TNBS), respectively. Three specific aims are proposed. Specific Aim 1 will characterize chemotype of functionally distinct classes of afferents in the pelvic nerve (PN) colorectal innervation. Specific Aim 2 will determine the histological location and morphological features of functionally distinct classes of afferents in te PN colorectal innervation. Specific Aim 3 will explore the underlying mechanisms for enhanced neural encoding of colorectal afferents using computational simulation. Specific Aim 4 will explore the possible translation of outcomes from the foregoing studies into clinic targets for management of colorectal pain and hypersensitivity by studying human intestinal afferents in vitro. The combined functional, chemotypical, and morphological approaches will allow generation of new information about channels/receptors that contribute to afferent sensitization and, for the first time, reveal histological/morphological features of colorectal receptive endings Experimental data will be used to construct and validate a computational simulation, which will allow exploration of the putative mechanism(s) for sensitization in each functionally distinct afferent class. The outcomes of the proposed experiments have the potential to guide strategies for development of pharmacological compounds that possess colorectal afferent sub-class specificity.

描述（由申请人提供）：估计肠易激综合症（IBS）影响美国15％的人口，对生活质量以及年度直接和间接医疗保健费用负面影响约为300亿美元。疼痛是IBS的特征症状，也是患者访问胃肠病医生的主要原因。积累的证据表明，对于IBS相关的疼痛和超敏反应，必须提高结直肠传入的外围感觉输入（即传入敏化）。拟议的研究的目的是研究分子/神经化学身份（“化学型”）和结直属性的传入类别的组织学位置，从中，将揭示有关传入敏化机制的信息，这些信息有助于结直肠超敏。具体而言，在连续性中使用神经和脊髓的小鼠结肠菌的新型外体制备将对传入电生理学的功能性研究和化学型评估和传入结束解剖结构进行。研究将在分别通过Zymosan或三位一苯磺酸（TNBS）内的内脏超敏反应的长期模型中进行。提出了三个具体目标。特定的目标1将表征骨盆神经（PN）结直肠神经上功能不同类别的传入的化学型。特定的目标2将确定TE PN结直肠神经支配中功能不同类别的传入的组织学位置和形态学特征。具体目标3将探索使用计算模拟增强结直肠传入神经编码的基本机制。特定的目标4将通过在体外研究人类肠道传入剂来探索从上述研究到治疗结直肠疼痛和超敏反应的临床目标的结果的可能转化。结合功能，化学型和形态学方法将允许生成有关导致传入敏化的通道/受体的新信息，这些信息/受体首次揭示了结直肠接受结尾的组织学/形态学特征实验数据将用于构建和验证一个计算模拟，从而允许探索采集机制（S）在各种阶段（S）中的探索。所提出的实验的结果具有指导具有结直肠传入子类特异性的药理学化合物的策略。