Brain Bladder Interactions in IC/PBS

总体描述（由申请人提供）：间质性膀胱炎/膀胱疼痛综合征（IC/PBS）是一种常见的慢性膀胱综合征，特征为膀胱疼痛和不适（尿急）以及排尿频率增加。它是一个更大的慢性功能性疼痛疾病组的一部分，其中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点是它们是多因素的，临床上表现为生物学和心理学表型的马赛克。尽管密集的，主要是靶器官为基础的药物开发工作，现有的治疗是不令人满意的。目前的提案由来自胃肠病学和泌尿学的经验丰富的高级研究人员共同指导，建立在这种跨学科观点的基础上，旨在描述生物和环境脆弱性因素的相互作用，以塑造行为和神经生物学内表型，并最终在IC/PBS中形成临床表型。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是一项在IC/PBS患者（以及早期生活和慢性应激的啮齿动物模型）的小型队列中进行的临床/转化研究，旨在表征几种神经生物学和行为内表型，并确定其与基因多态性的关系。项目3是在IC/PBS患者和相同啮齿动物应激模型中进行的基础科学研究，旨在研究改变的去甲肾上腺素能/SNS信号传导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，由泌尿学，胃肠病学，流行病学和神经科学等跨学科的研究人员组成的小组进行，他们可以使用已建立的基础设施来研究神经内脏相互作用，并且在功能性疼痛综合征的研究方面具有丰富的经验，包括IBS和IC/PBS。这些项目彼此密切互动，项目调查人员一直在与大批研究人员和附属机构互动。通过将IC/PBS的复杂的、基于神经元的综合征解构为不同的神经生物学和行为内表型，我们预计将识别出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.