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.

项目摘要储存较低的尿路症状（LUTS），其中包括泌尿紧急，频率，夜尿，痛苦排尿和膀胱压力/不适，请参阅膀胱无法尿液时的患者经历适当。这些高度普遍的症状是慢性和衰弱的，实质上会降低身体活动和生活质量。然而，尽管存储负担很大，但对公共卫生的负担很少这些症状的病理生理学，限制诊断，治疗和预防选择。人类藏有多元化的微生物群落，与健康的宿主共生但经常改变在疾病中。这些改变的作用尚不清楚，但安装研究表明微生物成分可能与人体组织相互作用以改变器官功能，组织渗透性，甚至中枢神经系统反应性。我们和其他人使用了新颖的，最先进的DNA测序方法来识别细菌和居住在尿路内的真菌并描述患者尿微生物群落的全球差异带有存储luts。我们尚未了解这些差异如何影响膀胱病理生理学，但是我们初步数据表明，这些微生物群落的转移是基础或反映储存LUTS症状的基础并与局部和全身性炎症增加相关。我们假设这些相互作用发生了变化宿主的社区改变了局部和系统性炎症，并增加了膀胱的免疫学激活尿路上皮细胞，产生特定尿症状的炎症特征。基于与其他炎症性疾病相似，我们假设这种炎症在易感宿主具有失调的微生物识别，可能是由宿主遗传差异介导的对微生物成分的响应。使用最先进的微生物分析技术，我们将确定与患者储存相关的细菌和真菌群落的变化。我们还将确定炎症标志物和尿路上皮激活的疾病相关变化，并将这些发现与特定的微生物特征和症状模式。我们将执行遗传的目标表征与微生物的炎症反应相关的多态性，以探讨在这些条件下的宿主敏感性。以前很少有研究检查了尿菌群。这个建议是第一个将多OMIC数据集与临床元数据相结合以发现临床上有用的疾病的人标记物，微生物和炎症，将它们置于疾病机制的背景下，并寄托了风险因素。这项研究可能会促进对储存的更全面的理解，识别可以用作新治疗剂靶标的分子途径。来自这项研究将对IC/PBS诊断和治疗产生重大影响，并提供重要的进一步研究的起点检查了这种具有挑战性和难治性疾病的病理生理学。