Brain Bladder Interactions in IC/PBS

总体描述(由申请人提供)：间质性膀胱炎/痛性膀胱综合征(IC/PBS)是一种常见的慢性膀胱综合征，以膀胱疼痛和不适(紧迫感)和尿频增加为特征。它是一大类慢性功能性疼痛障碍的一部分，这些疾病还包括肠易激综合征(IBS)和纤维肌痛(FM)等常见疾病。这些综合征的一个共同特征是它们是多因素的，在临床上表现为生物和心理表型的马赛克。尽管进行了紧张的、主要针对器官的药物开发努力，但现有的治疗方法并不令人满意。目前的建议由来自胃肠病和泌尿学的经验丰富的高级研究人员共同指导，建立在这一跨学科观点的基础上，旨在表征生物和环境易损性因素之间的相互作用，以塑造IC/PBS的行为和神经生物学内表型，并最终形成临床表型。该提案的3个项目涉及以下3个领域：项目1是一个有针对性的流行病学项目，研究遗传标记、早期生活经历和成人压力对IC/PBS症状和共病疼痛综合征的影响。项目2是在一小群IC/PBS患者(以及早期生活和慢性应激的啮齿动物模型)中进行的临床/翻译研究，旨在表征几种神经生物学和行为内表型，并确定它们与基因多态的关系。项目3是在IC/PBS患者和相同的啮齿动物应激模型中进行的基础科学研究，旨在研究去甲肾上腺素/SNS信号改变对尿路上皮和脊髓神经胶质细胞的细胞和分子后果。这些项目涉及广泛的流行病学、心理生理学、神经生物学和分子技术，由从泌尿学、胃肠病学、流行病学和神经科学的跨学科研究小组实施，他们拥有研究神经内脏相互作用的成熟基础设施，并在功能性疼痛综合征(包括IBS和IC/PBS)的研究方面拥有丰富的经验。这些项目相互之间互动密切，项目调查人员一直在与一大批研究人员和附属机构互动。通过将复杂的、以症状为基础的IC/PBS综合征分解为不同的神经生物学和行为内表型，我们预计可以确定更合理的药物开发靶点，并最终开发出更有效的治疗方法。

DESCRIPTION, OVERALL (provided by applicant): Interstitial cystitis/painful bladder syndrome (IC/PBS) is a common chronic bladder syndrome characterized by bladder pain and discomfort (urgency) and increased frequency of urination. It is part of a larger group of chronic functional pain disorders, which also include such common disorders as irritable bowel syndrome (IBS) and fibromyalgia (FM). A common feature of these syndromes is that they are multifactorial and present clinically as a mosaic of biologic and psychologic phenotypes. Despite intense, largely target organ-based drug development efforts, existing treatments are unsatisfactory. The current proposal, co-directed by experienced, senior investigators from gastroenterology and urology builds on this interdisciplinary view and aims to characterize the interactions of biological and environmental vulnerability factors to shape behavioral and neurobiological endophenotypes, and ultimately clinical phenotypes in IC/PBS. The 3 Projects of the proposal address the following 3 areas: Project 1 is a targeted epidemiological project studying the impact of genetic markers, early life experiences and adult stress on IC/PBS symptoms and comorbid pain syndromes. Project 2 is a clinical/translational study in a small cohort of IC/PBS patients (and in a rodent model of early life and chronic stress) which aims at characterizing several neurobiological and behavioral endophenotypes, and identifying their relationship to gene polymorphisms. Project 3 is a basic science study in IC/PBS patients and in the same rodent stress model which aims at studying cellular and molecular consequences of altered noradrenergic/SNS signaling on the urothelium and spinal glial cells. These projects involve a wide range of epidemiological, psychophysiological, neurobiological and molecular techniques, performed by an interdisciplinary group of investigators ranging from Urology, Gastroenterology, Epidemiology and Neuroscience, who have access to an established infrastructure to study neurovisceral interactions, and who have extensive previous experience in the study of functional pain syndromes, including IBS and IC/PBS. The projects closely interact with each other, and project investigators have been interacting with a large group of researchers and affiliated institutions. By deconstructing the complex, symptom-based syndrome of IC/PBS into distinct, neurobiological and behavioral endophenotypes, we anticipate the identification of more rationale drug development targets, and ultimately the development of more effective therapies.