The Urinary Microbiota and Host Inflammation in Lower Urinary Tract Symptoms

泌尿微生物群和下尿路症状中的宿主炎症

基本信息

批准号：
10450187
负责人：
A. Lenore Ackerman
金额：
$ 16.78万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450187
关键词：
Affect Anti-Inflammatory Agents Atypical lymphocyte Bacteria Biochemical Bladder Bladder Urothelial Cell Characteristics Chronic Classification Clinical Coculture Techniques Communities DNA sequencing Data Data Set Development Diagnosis Disease Disease Marker Etiology Foundations Frequencies Functional disorder Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genotype Hemostatic function Human Immune response Immune system Immunoassay Immunologics In Vitro Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interstitial Cystitis Investigation Lead Link Lower urinary tract Lymphocyte Function Mediating Metadata Methods Microbe Molecular Neuraxis Nocturia Organ Other Genetics Overactive Bladder Pain Pathogenesis Pathogenicity Pathway interactions Patients Pattern Permeability Persons Physical activity Physiology Plasma Population Population Heterogeneity Predisposition Prevention Prevention strategy Process Prognostic Marker Public Health Quality of life Refractory Disease Reporting Research Resources Ribosomal DNA Risk Factors Role Severity of illness Susceptibility Gene Symbiosis Symptoms Syndrome System Systems Biology Techniques Therapeutic Therapeutic Agents Tissues Urinary tract Urination Urine Urology Urothelium Variant Woman accurate diagnosis associated symptom base bladder pain burden of illness chemokine clinical phenotype cytokine data integration diagnostic biomarker diagnostic criteria disorder risk dysbiosis experience fungus host-microbe interactions human tissue immune activation in vitro Model in vivo inflammatory marker insight lower urinary tract symptoms microbial microbial community microbial host microbial signature microbiome microbiota micturition urgency multiple omics new therapeutic target next generation sequencing novel novel therapeutic intervention novel therapeutics pathobiont persistent symptom pressure prevent receptor response study population symptom cluster symptomatology systemic inflammatory response urinary urologic

项目摘要

PROJECT SUMMARY Storage lower urinary tract symptoms (LUTS), which include urinary urgency, frequency, nocturia, painful urination, and bladder pressure/discomfort, refer to patient experiences when the bladder is unable hold urine appropriately. These highly prevalent symptoms are chronic and debilitating, substantially degrading physical activity and quality of life. Yet despite the heavy burden of storage LUTS on public health, little is understood of the pathophysiology of these symptoms, limiting diagnosis, treatment, and prevention options. Humans harbor diverse microbial communities that live in symbiosis with healthy hosts but are frequently altered in disease. The role of these alterations is unclear, but mounting research suggests that microbial components may interact with human tissue to alter organ function, tissue permeability, and even central nervous system responsivity. We and others have used novel, state-of-the-art DNA sequencing methods to identify bacteria and fungi residing within the urinary tract and describe global differences in urinary microbial communities in patients with storage LUTS. We have yet to understand how these differences impact bladder pathophysiology, but our preliminary data suggest that shifts in these microbial communities underlie or reflect storage LUTS symptoms and correlate with increased local and systemic inflammation. We postulate that interactions of these changed communities with the host alter local and systemic inflammation and increase immunologic activation of bladder urothelial cells, generating inflammatory signatures characteristic of specific urinary symptoms. Based on similarities to other inflammatory diseases, we hypothesize that this inflammation becomes pathogenic in susceptible hosts with dysregulated microbial recognition, possibly mediated by genetic differences in host responsiveness to microbial components. Using state-of-the-art microbial profiling techniques, we will identify changes in urinary bacterial and fungal communities linked to storage LUTS in patients. We will also identify disease-associated variations in inflammatory markers and urothelial activation and associate these findings with specific microbial signatures and symptom patterns. We will perform a targeted characterization of genetic polymorphisms associated with dysregulated inflammatory responses to microbes to explore the contribution of host susceptibility in these conditions. Few previous studies have examined the urinary microbiota; this proposal is the first to integrate multi-omic datasets with clinical metadata to allow the discovery of clinically useful disease markers, microbial and inflammatory, and place them into the context of disease mechanisms and host risk factors. This study may promote a more comprehensive understanding of storage LUTS pathogenesis, identifying the molecular pathways that could serve as targets of new therapeutic agents. Positive results from this study would have significant implications for IC/PBS diagnosis and treatment and provide an important starting point for further studies examining the pathophysiology of this challenging and refractory disease.

项目概要储存性下尿路症状 (LUTS)，包括尿急、尿频、夜尿、尿痛排尿和膀胱压力/不适，指膀胱无法容纳尿液时患者的经历适当地。这些非常普遍的症状是慢性的、令人衰弱的、严重损害身体的活动和生活质量。然而，尽管存储 LUTS 对公共健康造成了沉重负担，但人们对它知之甚少。这些症状的病理生理学限制了诊断、治疗和预防的选择。人类拥有多种微生物群落，它们与健康宿主共生，但经常发生改变在疾病中。这些改变的作用尚不清楚，但越来越多的研究表明微生物成分可能与人体组织相互作用，改变器官功能、组织通透性，甚至中枢神经系统响应能力。我们和其他人使用新颖、最先进的 DNA 测序方法来识别细菌和居住在泌尿道内的真菌并描述患者泌尿微生物群落的整体差异与存储LUTS。我们尚未了解这些差异如何影响膀胱病理生理学，但我们的研究初步数据表明，这些微生物群落的变化是储存 LUTS 症状的基础或反映并与局部和全身炎症增加相关。我们假设这些之间的相互作用发生了变化与宿主的社区改变局部和全身炎症并增加膀胱的免疫激活尿路上皮细胞，产生特定泌尿系统症状特征的炎症特征。基于与其他炎症性疾病相似，我们假设这种炎症在微生物识别失调的易感宿主，可能是由宿主遗传差异介导的对微生物成分的反应性。使用最先进的微生物分析技术，我们将识别尿液细菌和真菌群落的变化与患者储存 LUTS 相关。我们还将确定炎症标志物和尿路上皮活化的疾病相关变化，并将这些发现与特定的微生物特征和症状模式。我们将对基因进行有针对性的表征与微生物炎症反应失调相关的多态性，以探索宿主在这些条件下的易感性。之前很少有研究检查尿液微生物群。这个提议是第一个将多组学数据集与临床元数据集成以发现临床有用疾病的公司标记物、微生物和炎症，并将它们置于疾病机制和宿主风险的背景下因素。这项研究可能会促进对存储LUTS发病机制的更全面的了解，确定可以作为新治疗药物靶标的分子途径。积极的结果来自这项研究将对 IC/PBS 诊断和治疗产生重大影响，并提供重要的参考进一步研究这种具有挑战性和难治性疾病的病理生理学的起点。