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

该项目的长期目标是鉴定和表征与细胞因子相互作用的内表型。 与基因和早期环境影响，在成人中产生IC/PBS的临床综合征， 病人将IC/PBS的复杂的基于神经元的综合征分解为神经生物学内表型， 基因与早期环境相互作用的影响，将增强我们对基因的理解。 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， 这是开发有效治疗方法所必需的。使用心理物理评估 描述疼痛敏感性的技术，评估情绪唤起的神经生理学测试， 功能性脑成像技术，以确定潜在的大脑回路，该项目旨在追求这一点 在150名IC/PBS患者（和150名对照）和啮齿动物应激模型中，3个特定目标的长期目标：A. 在IC/PBS中表征参与骨盆疼痛处理和内源性疼痛抑制的脑回路。B。 表征IC/PBS中涉及情绪唤醒和中枢疼痛易化的脑机制。C. 描述出生前和成年压力的啮齿动物模型中的脑回路。神经生物学内表型 在每一个目标中确定的基因多态性将与参与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，然后我们将确定参与加工和内源性的脑回路的变化 抑制疼痛。在目标B中，我们将描述听觉惊吓反射的情感调节的作用， 伤害性脊髓反射（RIM）反应，以及情绪唤醒回路产生疼痛抑制， 便利化在目标C中，我们将描述产前应激和成人慢性应激对大脑的影响。 对自由活动大鼠膀胱扩张的反应。该项目对RFA的要求做出了高度响应 研究患者的小队列以建立稳健的表型，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。它与以下方面密切相互作用， 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， 其解决了与内表型相关的脊髓和外周（膀胱）变化。

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.