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Loss of Bladder Control Following Recurrent Infections

反复感染后膀胱失去控制

基本信息

批准号：
10368136
负责人：
Soman N Abraham
金额：
$ 40.98万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-16 至 2024-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368136
关键词：
Acute Antibodies Anxiety Back Pain Bacterial Infections Biological Markers Bladder Bladder Control Bladder Dysfunction C Fiber Cells Clinical Research Defect Degenerative polyarthritis Detection Exhibits Exposure to Frequencies Ganglia Growth Growth Factor Hyperactivity Hyperplasia Immune Immune response Immunologic Memory Impairment Infection Link Mechanics Mediator of activation protein Morbidity - disease rate Motor Mus Muscle Contraction Nature Nerve Nerve Fibers Nerve Growth Factor Receptors Nerve Growth Factors Neuraxis Neurons Nociception Organ Outcome Overactive Bladder Pain Pelvis Property Recording of previous events Recurrence Risk Factors Role Sensory Severities Source Therapeutic Urinary tract infection Urination Urine Uropathogenic E. coli Wild Type Mouse afferent nerve antagonist cholinergic density detrusor muscle experience mast cell monocyte mouse model neurotransmission neurotrophic factor pathogen preclinical study pressure prevent psychologic recruit recurrent infection response spinal nerve posterior root therapeutic target urinary

项目摘要

Current estimates for the annual treatment of UTIs in the US including recurrences and their complications exceed $3.5 billion. A significant number of UTIs are recurrent (recUTIs), with the same subject experiencing multiple bouts of infection. A frequent outcome of recUTIs is loss in bladder control which is manifested as increased urgency and frequency accompanied by loss of bladder capacity. In spite of the severe discomfort and anxiety associated with this condition, the underlying basis for bladder impairment has remained unresolved. In an experimental mouse model of UPEC-induced recUTIs, we observed exuberant sprouting of sensory and sympathetic nerves was observed in the mouse bladder, which closely paralleled increased bladder frequency and reduced bladder capacity in the infected mice. These observations suggest that bladder nerve fibers actively respond to bacterial infections and these responses could potentially contribute to loss of bladder dysfunction. Since a known determinant of nerve cells sprouting in the bladder is nerve growth factor (NGF) we looked for possible sources of this growth factor. We have identified mast cells (MCs) and monocytes as putative cellular sources of NGF as mice subjected to recUTIs contain large number of recruited monocytes compared to naïve mice and MC deficient mice do not any loss of bladder control even after recUTIs. Therefore, we hypothesize that the loss of bladder control after recUTIs, is the direct result of nerve fiber hyperplasia which is induced by NGF and other neurotrophic factors produced by local MCs and MC recruited monocytes. We further hypothesize that it is possible to prevent loss of bladder control in mice subjected to recUTIs by therapeutic targeting of NGF and other neurotrophic factors. To validate these notions, we have proposed the following specific aims: (i) Establish a clear link between neuronal sprouting and loss of bladder control in mice subjected to recUTIs;; (iii) Examine the role of neurotrophic factors in bladder dysfunction following recUTIs and the effect of targeting these factors to protect and even reverse bladder dysfunction (iii) Investigate the contribution of MCs to neuronal sprouting and bladder impairment.

目前对美国UTI年度治疗的估计，包括复发性及其并发症超过35亿美元。相当数量的UTI是复发性的（recUTI），同一受试者经历多次感染。复发性UTI的常见结果是丧失膀胱控制，表现为紧迫性和频率增加，伴随着损失膀胱容量。尽管与这种情况相关的严重不适和焦虑，膀胱损伤的潜在基础尚未解决。在一项实验中，在UPEC诱导的RecUTIs小鼠模型中，我们观察到感觉和在小鼠膀胱中观察到交感神经，膀胱频率和膀胱容量减少。这些观察结果表明膀胱神经纤维对细菌感染有积极反应，可能潜在地导致膀胱功能障碍的丧失。由于已知的神经功能障碍的决定因素细胞发芽在膀胱是神经生长因子（NGF），我们寻找可能的来源，我们已经确定肥大细胞（MC）和单核细胞作为假定的细胞来源因为与对照组相比，经历recUTI的小鼠含有大量募集的单核细胞，幼稚小鼠和MC缺陷小鼠即使在recUTI后也没有任何膀胱控制的丧失。因此，我们假设复发性尿路感染后膀胱控制的丧失是以下因素的直接结果：神经纤维增生是由NGF和其他神经营养因子引起的，局部MC和MC募集单核细胞。我们进一步假设，通过治疗性靶向NGF和其他药物治疗recUTI小鼠的膀胱控制丧失为了验证这些概念，我们提出了以下具体目标：（i）建立小鼠神经元发芽和膀胱控制丧失之间的明确联系，（iii）检查神经营养因子在recUTI后膀胱功能障碍中的作用以及靶向这些因子以保护甚至逆转膀胱功能障碍的作用（iii）研究MC对神经元发芽和膀胱损伤的贡献。