Molecular Characterization Of A Large Cross-Sectional And Longitudinal Collection of Patients To Investigate Disease Progression in IC/BPS

对大量横断面和纵向患者样本进行分子表征，以研究 IC/BPS 中的疾病进展

• 批准号: 10397556
• 负责人: STEPHEN WALKER
• 金额: $ 23.25万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397556
• 关键词: Anesthetics; Biological; Biopsy; Biopsy Specimen; Bladder; Bladder Diseases; Bladder Urothelium; Bladder mucosa; Blood; Characteristics; Classification; Clinic; Clinic Visits; Clinical; Clinical Data; Collection; Data; Diagnosis; Diagnostic tests; Disease; Disease Progression; Etiology; Functional disorder; Funding; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Individual; Interstitial Cystitis; Intracytoplasmic Sperm Injections; Life; Lower urinary tract; Measures; Methods; Molecular; Molecular Profiling; Molecular Target; Mucous Membrane; National Institute of Diabetes and Digestive and Kidney Diseases; Pain; Pain Disorder; Pathogenesis; Pathologic Processes; Pathway Analysis; Pathway interactions; Patients; Pelvic Pain; Phenotype; Predisposition; Process; Quality of life; Questionnaires; Research; Resolution; Sampling; Scheme; Severity of illness; Specimen; Subgroup; Suggestion; Surrogate Markers; Symptoms; Syndrome; Testing; Time; Tissues; Training; Transcript; Treatment Efficacy; Urologic Diseases; Validation; Variant; Visit; Work; base; case control; chronic pelvic pain; clinical phenotype; clinically relevant; comorbidity; disease heterogeneity; disorder subtype; individual patient; interdisciplinary approach; molecular phenotype; pain score; pain symptom; patient population; patient stratification; patient subsets; peripheral blood; predictive signature; prospective; regenerative therapy; repository; response; specific biomarkers; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; urologic

PROJECT SUMMARY The studies proposed here represent a continuation of our molecular and clinical phenotyping work in a large and diverse interstitial cystitis/bladder pain syndrome (IC/BPS) patient population. We present preliminary data suggesting that IC/BPS comprises at least two distinct phenotypic subpopulations; one characterized as a bladder-centric disease process and the other characterized as a systemic pain syndrome. The significant variability in symptoms and associated syndromes (i.e. disease heterogeneity as well as disease severity) among IC/BPS patients contributes to the difficulty in developing targeted therapeutics. Therefore, we propose to leverage a large repository of retrospectively and prospectively collected unique clinical specimens (bladder biopsy tissue and peripheral blood from >400 IC/BPS patients and >100 non-IC controls) to identify molecular mechanisms that define patient subgroups. This will be accomplished by using a sophisticated molecular profiling scheme (weighted gene co-expression analysis network, WGCNA) to correlate the transcriptome with individual patient clinical data as an unbiased means to stratify patients into clinically relevant subgroups for which potential therapeutic targets will have been identified in the process. A second objective of these studies is, through gene expression profiling of longitudinally collected patient samples (bladder mucosal biopsies) compared with change/progression in patient clinical characteristics (e.g. duration of symptoms, pain and symptom scores on validated questionnaires, anesthetic bladder capacity), to identify molecular targets and biological pathways that are suggestive of disease progression in IC/BPS. To accomplish these objectives we propose three Specific Aims. Aim 1: Identification of molecular signatures that correlate with disease progression in IC/BPS. Analysis of tissues from 300 patients will provide a representative cross-section of the extensive phenotypic variability seen in IC/BPS. The use of unbiased weighted gene co-expression network analysis (WGCNA) will allow us to identify gene expression signatures that correlate with clinical features associated with disease progression. Aim 2: Identification of a blood-based molecular signature indicative of disease progression in IC/BPS. In this Aim we will evaluate blood collected from the same 300 IC/BPS patients (and 100 controls) in SA1 to identify a blood- based molecular signature that correlates with disease severity and is indicative of disease progression. We will also determine whether blood molecular signatures correlate with bladder mucosal molecular signatures, which may provide higher resolution phenotypic classification than current clinical measures. Aim 3: Identification of molecular signatures that predict disease progression in IC/BPS. We hypothesize that gene expression in the bladder mucosa of IC/BPS patients reflects disease status and that, over time, changes within an individual may indicate disease progression. We will identify groups of genes that predict disease progression using unbiased WGCNA of RNA-Seq data from longitudinal patient samples.

项目概要 这里提出的研究代表了我们在大范围内分子和临床表型分析工作的延续。 以及不同的间质性膀胱炎/膀胱疼痛综合征 (IC/BPS) 患者群体。我们提出初步 数据表明 IC/BPS 包含至少两个不同的表型亚群；一个特征为 以膀胱为中心的疾病过程，另一种特征为全身性疼痛综合征。显着的 症状和相关综合征的变异性（即疾病异质性以及疾病严重程度） IC/BPS 患者中的差异导致了开发靶向治疗的困难。因此，我们建议 利用回顾性和前瞻性收集的独特临床标本（膀胱 来自 >400 名 IC/BPS 患者和 >100 名非 IC 对照者的活检组织和外周血），以鉴定分子 定义患者亚组的机制。这将通过使用复杂的分子来实现 分析方案（加权基因共表达分析网络，WGCNA）将转录组与 个体患者的临床数据作为将患者分为临床相关亚组的公正手段 在此过程中将确定哪些潜在的治疗靶点。 这些研究的第二个目标是，通过纵向收集的患者的基因表达谱 样本（膀胱粘膜活检）与患者临床特征的变化/进展（例如， 症状持续时间、经过验证的问卷中的疼痛和症状评分、麻醉膀胱容量）， 识别提示 IC/BPS 疾病进展的分子靶点和生物途径。 为了实现这些目标，我们提出了三个具体目标。目标 1：分子鉴定 与 IC/BPS 疾病进展相关的特征。对 300 名患者的组织进行分析 将提供 IC/BPS 中广泛表型变异的代表性横截面。使用 无偏加权基因共表达网络分析 (WGCNA) 将使我们能够识别基因表达 与疾病进展相关的临床特征相关的特征。目标 2：识别 指示 IC/BPS 疾病进展的基于血液的分子特征。为了这个目标，我们将 评估从 SA1 中相同的 300 名 IC/BPS 患者（和 100 名对照）采集的血液，以确定血液- 与疾病严重程度相关并指示疾病进展的分子特征。我们将 还确定血液分子特征是否与膀胱粘膜分子特征相关， 这可以提供比当前临床测量更高分辨率的表型分类。目标 3： 鉴定预测 IC/BPS 疾病进展的分子特征。我们 假设 IC/BPS 患者膀胱粘膜中的基因表达反映了疾病状态，并且， 随着时间的推移，个体内部的变化可能表明疾病进展。我们将确定基因组 使用来自纵向患者样本的 RNA-Seq 数据的无偏 WGCNA 来预测疾病进展。

项目成果

Small-Fiber Polyneuropathy Is Prevalent in Patients With Interstitial Cystitis/Bladder Pain Syndrome.

小纤维多发性神经病在间质性膀胱炎/膀胱疼痛综合征患者中普遍存在。

• 发表时间: 2022-11-01
• 作者: Wolff, Dylan T;Xu, Raymond;Overholt, Tyler;Bassett, E Hadley;Ahn, Christine;Simon, Trang;Lee, Peyton;Badlani, Gopal;Matthews, Catherine A;Evans, Robert J;Walker, Stephen J
• 通讯作者: Walker, Stephen J