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：
10612716
负责人：
Soman N Abraham
金额：
$ 37.91万
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/10612716
关键词：
Acute Afferent Neurons Antibodies Anxiety Back Pain Bacterial Infections Biological Markers Bladder Bladder Control Bladder Dysfunction C Fiber Cells Central Nervous System Clinical Research Communication Defect Degenerative polyarthritis Detection Exhibits Exposure to Frequencies Ganglia Growth Growth Factor Hyperactivity Hyperplasia Immune Immune response Immunologic Memory Impairment Infection Link Mechanics Mediator Morbidity - disease rate Motor Neurons Mus Muscle Contraction Nature Nerve Nerve Fibers Nerve Growth Factor Receptors Nerve Growth Factors 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 response biomarker spinal nerve posterior root therapeutic target treatment response 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.

当前对美国UTI年度治疗的估计包括收入和并发症超过35亿美元。大量的UTI是经常性的（recutis），相同的主题经历了多种感染观点。经常的结果是损失膀胱控制表现为增加的紧迫性和频率膀胱容量。尽管与这种情况有严重的不适和焦虑，但膀胱损伤的基本基础尚未解决。在实验中 UPEC诱导的Recutis的小鼠模型，我们观察到了感觉和在小鼠膀胱中观察到交感神经，与平行的膀胱相似受感染小鼠的膀胱频率和膀胱容量降低。这些观察建议膀胱神经纤维积极应对广泛的感染和这些反应可能导致膀胱功能障碍的丧失。由于Neve的已知决定因素膀胱中发芽的细胞是NEVE生长因子（NGF），我们寻找了潜在的来源生长因子。我们已经将肥大细胞（MC）和单核细胞确定为推定的细胞源 NGF的小鼠受到恢复的小鼠，与幼稚的小鼠和MC缺乏小鼠即使在恢复后也不会损失膀胱控制。因此，我们假设恢复后的膀胱控制丧失是 NGF诱导的神经纤维增生和其他由其他神经营养工厂诱导的本地MC和MC招募了单核细胞。我们进一步假设它可能会阻止通过治疗靶向NGF和其他的小鼠膀胱控制损失神经营养因素。为了验证这些通知，我们提出了以下特定目的：（i）在受到的小鼠中建立神经元发芽与膀胱控制损失之间的明确联系 recutis ;; （iii）检查神经营养工厂在肾脏功能障碍中的作用以及针对这些因素保护甚至逆转膀胱功能障碍（III）的影响研究MC对神经元发芽和膀胱损伤的贡献。