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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：
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.

据目前的估计，美国东部地区尿路感染的年度治疗费用，包括复发和复发的费用。并发症将超过35亿美元。相当多的输尿管感染是复发性尿路感染(RecUTIs)。同一受试者正经历着多次尿路感染的发作。尿路感染的频繁发作和转归是一种潜在的损失。膀胱癌的控制主要表现为尿失禁的急迫性增加和尿失禁的频度增加。膀胱容量。尽管这种情况与严重的不适和焦虑有关，但仍是如此。膀胱肌功能减退的潜在基础问题仍然没有解决。小鼠是UPEC诱导的尿路感染的模型动物，我们观察到了它的感官细胞和细胞的旺盛萌发。在正常小鼠的膀胱中也观察到交感神经的存在，这与膀胱的增加密切相关。在感染的小鼠中，膀胱频率的改变和膀胱容量的降低。提示膀胱神经纤维应积极应对细菌感染，并控制这些反应。这可能会潜在地导致膀胱肌功能障碍的损失。自那以后，人们发现了一种已知的神经功能决定因素。在膀胱中萌发的细胞是一种神经生长因子(NGF)，我们一直在寻找这种情况的可能来源。生长因子。我们已经确定肥大细胞(MCs)和单核细胞是推测的主要细胞来源。与对照组相比，接受尿路感染的小鼠体内募集的单核细胞数量较多。天真的小鼠和MMC有缺陷的小鼠，即使在接受尿路感染后，也不会有任何明显的膀胱控制损失。因此，如果我们假设膀胱移植物抗凝治疗后膀胱癌的控制率下降，那就是膀胱移植物抗感染的直接后果。神经纤维增生是由神经生长因子和其他神经营养因子诱导的，是由神经营养因子产生的。当地的MCs和MMC招募了更多的单核细胞。我们进一步提出了假设，即它不可能被用来预防这种情况。在接受尿路感染治疗的小鼠中，通过靶向NGF基因和其他基因表达的治疗药物，使小鼠的膀胱功能丧失。神经营养因子。为了更好地验证这些概念，我们提出了以下几个具体的目标：(I)。在受影响的小鼠中，在神经元萌发能力和膀胱控制能力的丧失之间建立一个明确的联系。 (Iii)研究神经营养因子在尿路感染后膀胱功能障碍中的重要作用。而针对这些关键因素的治疗效果可能有助于保护患者，甚至逆转膀胱功能障碍。调查MCs对神经细胞发芽和膀胱功能损害的主要贡献。