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: 10153770
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153770
• 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.

项目摘要 这里提出的研究代表了我们的分子和临床表型的延续 以及各种间质性膀胱炎/膀胱疼痛综合征（IC/BPS）患者人群。我们提出初步 数据表明IC/BPS至少包括两个不同的表型亚群；一个被描述为 以膀胱为中心的疾病过程，另一种为全身性疼痛综合征。重要的 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） 在IC/BPS患者中，患者有助于开发靶向治疗剂的困难。因此，我们提出 利用回顾性和前瞻性收集的独特临床标本的大量存储库（膀胱 来自> 400个IC/BPS患者和> 100个非IC对照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完成 分析方案（加权基因共表达分析网络，WGCNA），将转录组与 个体患者临床数据作为一种无偏见的手段，将患者分类为临床相关的亚组 在此过程中将确定哪些潜在的治疗靶标。 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分析 与患者临床特征的变化/进展相比，样品（膀胱粘膜活检）（例如 症状的持续时间，疼痛和症状评分在经过验证的问卷中，麻醉膀胱容量） 确定暗示IC/BPS疾病进展的分子靶标和生物途径。 为了实现这些目标，我们提出了三个具体目标。目标1：识别分子 与IC/BPS中疾病进展相关的特征。分析300例患者的组织 将提供IC/BPS中广泛的表型变异性的代表性横截面。使用 无偏的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 基于血液的分子特征，指示IC/BPS疾病进展。在这个目标中，我们将 评估SA1中从相同300个IC/BPS患者（和100个对照组）收集的血液，以鉴定血液 基于与疾病严重程度相关的分子特征，表明疾病进展。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， 比目前的临床指标可以提供更高的分辨率表型分类。目标3： 鉴定可以预测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 随着时间的流逝，个体内部的变化可能表明疾病进展。我们将确定一群基因 使用纵向患者样本中RNA-Seq数据的无偏WGCNA预测疾病进展。