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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.

目前对美国尿路感染年度治疗的估计，包括复发率及其发生情况并发症超过 35 亿美元。大量尿路感染是复发性尿路感染 (recUTI)，其中同一对象经历多次感染。 recUTI 的常见结果是损失膀胱控制，表现为尿急和尿频增加，并伴有尿失禁膀胱容量。尽管这种情况会带来严重的不适和焦虑，膀胱损伤的根本原因仍未解决。在实验中 UPEC 诱导的 recUTI 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，其密切平行地增加受感染小鼠的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积极响应细菌感染以及这些反应可能会导致膀胱功能障碍的消失。由于已知的神经决定因素膀胱中发芽的细胞是神经生长因子（NGF），我们寻找其可能的来源生长因子。我们已确定肥大细胞 (MC) 和单核细胞为假定的细胞来源与接受 recUTI 的小鼠相比，NGF 含有大量招募的单核细胞幼稚小鼠和 MC 缺陷小鼠即使在复发性尿路感染后也不会丧失膀胱控制。因此，我们假设，再发尿路感染后膀胱失去控制是以下因素的直接结果：由 NGF 和其他神经营养因子产生的神经纤维增生本地 MC 和 MC 招募单核细胞。我们进一步假设可以防止通过 NGF 和其他药物的治疗靶向，使患有复发性泌尿道感染的小鼠膀胱失去控制神经营养因子。为了验证这些想法，我们提出了以下具体目标：(i) 在小鼠中建立神经元出芽和膀胱控制丧失之间的明确联系复发性尿路感染；；(iii) 检查神经营养因子在复发性尿路感染后膀胱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的效果 (iii) 研究 MC 对神经元出芽和膀胱损伤的贡献。