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.

项目摘要 这里提出的研究代表了我们在大规模的分子和临床表型研究中的继续。 和不同的间质性膀胱炎/膀胱疼痛综合征（IC/BPS）患者人群。我们提出了初步的 数据表明IC/BPS包括至少两个不同的表型亚群;一个表征为 一种是以膀胱为中心的疾病过程，另一种是以全身疼痛综合征为特征。的重大 症状和相关综合征的变异性（即疾病异质性和疾病严重程度） IC/BPS患者中的高血压导致了开发靶向治疗的困难。所以我们提出 为了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对照的活组织检查组织和外周血），以鉴定分子生物学特征。 定义患者亚组的机制。这将通过使用一种复杂的分子 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无偏倚方法，将患者分为临床相关亚组， 哪些潜在的治疗靶点将在该过程中被确定。 这些研究的第二个目的是，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（例如， 症状持续时间、经验证问卷的疼痛和症状评分、麻醉膀胱容量）， 确定提示IC/BPS疾病进展的分子靶点和生物学途径。 为了实现这些目标，我们提出了三个具体目标。目的1：分子鉴定 与IC/BPS中疾病进展相关的特征。300例患者的组织分析 将提供IC/BPS中观察到的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：确定 基于血液的分子特征指示IC/BPS中的疾病进展。在这个目标中，我们将 评价从SA 1中相同的300例IC/BPS患者（和100例对照）采集的血液，以确定血液- 基于与疾病严重程度相关并指示疾病进展的分子标记。我们将 还确定血液分子标记是否与膀胱粘膜分子标记相关， 其可以提供比当前临床测量更高分辨率的表型分类。目标三： 识别预测IC/BPS疾病进展的分子特征。我们 假设IC/BPS患者膀胱粘膜中基因表达反映疾病状态， 随着时间的推移，个体内的变化可能表明疾病的进展。我们将识别出 使用来自纵向患者样本的RNA-Seq数据的无偏WGCNA预测疾病进展。

项目成果

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

• DOI: 10.1097/spv.0000000000001240
• 发表时间: 2022-11-01
• 期刊: Urogynecology (Philadelphia, Pa.)