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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.

目前估计每年治疗尿路感染在美国包括复发和他们的