Neurobiological endophenotypes & gene-environment interactions in IC/PBS & in a

神经生物学内表型

• 批准号: 7571862
• 负责人: Emeran A Mayer
• 金额: $ 41.81万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571862
• 关键词: Address; Adrenergic Receptor; Adult; Affective; Arousal; Arts; Bladder; Brain; Brain imaging; Candidate Disease Gene; Chronic; Chronic stress; Clinical; Complex; Databases; Development; Dimensions; Emotional; Environment; Epidemiologic Studies; Event; Face; Female; Figs - dietary; Functional disorder; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Goals; Human; Hyperalgesia; Image; Imaging Techniques; Interstitial Cystitis; Investigation; Irritable Bowel Syndrome; Life; Life Stress; Lower Extremity; Magnetic Resonance Imaging; Mental disorders; Modeling; Mood Disorders; Neurobiology; Nociception; Nociceptive Reflex; Pain; Patients; Pelvic Pain; Peripheral; Phenotype; Physiological; Play; Process; Psychophysiology; Rattus; Reflex action; Research; Rodent; Rodent Model; Role; Shapes; Signal Transduction; Spinal; Stimulus; Stress; Symptoms; Syndrome; System; Techniques; Testing; Time; Visceral; base; central pain; chronic pain; cognitive function; cognitive modulation of pain; cohort; coping; endophenotype; gene environment interaction; genetic association; human study; human subject; insight; neurophysiology; pain inhibition; prenatal; prenatal stress; psychosocial; response; spinal reflex; urinary

The longterm goal of this project is the identification and characterization of endophenotypes which interact with genes and with early environmental effects to produce the clinical syndrome of IC/PBS in the adult patient. Dissecting the complex symptom-based syndrome of IC/PBS into neurobiological endophenotypes, which are shaped by gene-early environment interactions, will enhance our understanding of its pathophysiology, of its relationship with other functional pain syndromes and affective disorders, and is required for the development of effective treatment approaches. Using psychophysical assessment techniques to characterize pain sensitivity, neurophysiological tests to asess emotional arousal, and functional brain imaging techniques to identify underlying brain circuits, this project aims to pursue this longterm goal in 3 specific aims in 150 IC/PBS patients (and 150 controls) and in a rodent stress model: A. Characterize brain circuits involved in pelvic pain processing and endogenous pain inhibition in IC/PBS. B. Characterize brain mechanisms involved in emotional arousal and central pain facilitation in IC/PBS. C. Characterize brain circuits in a rodent model of prenatal and adult stress. Neurobiological endophenotypes identified in each aim will be correlated with gene polymorphisms of signaling systems involved in pain processing and modulation, and in emotional and cognitive function, and early adverse life events. In Aim A, we will first characterize somatic pain sensitivity in IC/PBS using different types of pain stimuli. Using these pain stimuli, we will then identify alterations in brain circuits involved in the processing and endogenous inhibition of pain. In Aim B, we will characterize the role of affective modulation of the aoustic startle reflex, of a nociceptive spinal reflex (RIM) response, and of emotional arousal circuits in producing pain inhibition and facilitation. In Aim C, we will characterize the effect of prenatal stress, and of adult chronic stress on brain responses to bladder distension in the freely moving rat. This project is highly responsive to the RFA request to study small cohorts of patients to establish robust pheontypes, and to characterize the role of biologic, psychosocial and genetic vulneraility factors in IC/PBS. It interacts closely and in a synergistic fashion with Project 1 (which addresses the same question with a targeted epidemiological study) and with Project 3, which addresses spinal and peripheral (bladder) changes associated with the endophenotypes.

该项目的长期目标是鉴定和表征相互作用的内表型 与基因和早期环境影响一起产生成人 IC/PBS 临床综合征 病人。将 IC/PBS 复杂的基于症状的综合征剖析为神经生物学内表型， 由基因与早期环境相互作用塑造的，将增强我们对其的理解 病理生理学，其与其他功能性疼痛综合征和情感障碍的关系，并且是 开发有效的治疗方法所必需的。使用心理物理评估 表征疼痛敏感性的技术，评估情绪唤醒的神经生理学测试，以及 功能性脑成像技术来识别潜在的大脑回路，该项目旨在实现这一目标 150 名 IC/PBS 患者（和 150 名对照）和啮齿动物应激模型中 3 个具体目标的长期目标：A. 表征 IC/PBS 中参与盆腔疼痛处理和内源性疼痛抑制的脑回路。 B. 描述 IC/PBS 中涉及情绪唤醒和中枢疼痛促进的大脑机制。 C. 描述产前和成年压力的啮齿动物模型中的大脑回路。神经生物学内表型 每个目标中确定的目标将与涉及疼痛的信号系统的基因多态性相关 处理和调节，情绪和认知功能，以及早期不良生活事件。在目标A中， 我们将首先使用不同类型的疼痛刺激来表征 IC/PBS 中的躯体疼痛敏感性。使用这些 疼痛刺激，然后我们将识别参与处理和内源性的大脑回路的变化 抑制疼痛。在目标 B 中，我们将描述声惊惊反射的情感调节的作用， 伤害性脊髓反射（RIM）反应，以及产生疼痛抑制和情绪唤醒回路 便利化。在目标 C 中，我们将描述产前压力和成年慢性压力对大脑的影响 自由活动的大鼠对膀胱扩张的反应。该项目对 RFA 请求的响应非常迅速 研究小群患者以建立稳健的表型，并表征生物制剂的作用， IC/PBS 中的心理社会和遗传脆弱性因素。它以协同的方式与 项目 1（通过有针对性的流行病学研究解决同一问题）和项目 3， 它解决了与内表型相关的脊柱和外周（膀胱）变化。