PCB induced neurogenic inflammation mediates bladder dysfunction

PCB诱导的神经源性炎症介导膀胱功能障碍

• 批准号: 10515288
• 负责人: Kimberly Preston Keil Stietz
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10515288
• 关键词: Address; Adult; Adverse effects; Affect; Afferent Neurons; Age; Automobile Driving; Axon; Bladder; Bladder Control; Bladder Dysfunction; California; Central Nervous System; Child; Communication; Data; Deterioration; Development; Developmental Biology; Disease; Environment; Environmental Pollutants; Environmental Risk Factor; Epithelial Cells; Exposure to; Female; Frequencies; Functional disorder; Goals; Health Care Costs; Hydroxylation; Image; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Knowledge; Lactation; Link; Mediating; Mentors; Methods; Microelectrodes; Microfluidic Microchips; Modeling; Monitor; Mothers; Mus; Nerve Fibers; Neurobiology; Neurodevelopmental Disorder; Neurogenic Inflammation; Neurons; Neurotoxins; Output; Pain; Parents; Pathogenesis; Peripheral; Peripheral Nervous System; Polychlorinated Biphenyls; Population; Predisposition; Pregnancy; Pregnant Women; Purinoceptor; Quality of life; Research; Research Personnel; Risk; Role; Sensory; Serum; Severities; Signal Transduction; Spinal Ganglia; Symptoms; Testing; Therapeutic; Training; Urination; Urine; Urothelium; Woman; Work; afferent nerve; antagonist; awake; career; cellular targeting; cytokine; density; early life exposure; environmental chemical; experience; follow-up; high risk population; in utero; in vitro testing; in vivo; inflammatory marker; innovation; lower urinary tract symptoms; male; men; mother nutrition; nerve supply; neuronal cell body; neurotoxicology; new therapeutic target; novel; offspring; pharmacologic; prevent; prophylactic; risk mitigation; screening; success; two-photon; urinary; young adult

Lower urinary tract symptoms (LUTS) affect men and women of all ages, resulting in significant healthcare costs and reduced quality of life. Bladder inflammation is a common cause of LUTS, which results in pain, increased urgency and frequency of urination. Existing therapies only moderate symptoms; they do not treat their underlying basis. The development of new and more effective methods to treat or prevent LUTS is stymied by our incomplete understanding of how urinary function is acquired and why it deteriorates. While environmental factors are implicated in the pathogenesis of many diseases, whether they determine individual risk for LUTS is understudied. The goal of this project is to test the novel mechanistic hypothesis that developmental PCB exposure induces purinergic signaling via inflammatory mechanisms, resulting in increased afferent nerve activity and bladder voiding dysfunction. PCBs are known central nervous system neurotoxicants, but their effects on the peripheral nervous system, which is critically involved in bladder function, are largely unknown. To test this hypothesis, I will expose mice to a mixture of PCBs in the maternal diet throughout gestation and lactation. The PCB mix mimics the proportions of the top 12 PCB congeners found in the serum of mothers in California who are at risk for having a child with a neurodevelopmental disorder. Compelling preliminary evidence implicates inflammation and purinergic signaling as a mechanism by which early life exposure to PCBs influences young adult urinary function. I propose to build upon my previous research experience by leveraging the environment and expertise of Dr. Lein and Dr. Bjorling to fill gaps in my training that will facilitate my successful completion of the following specific aims testing the hypotheses that: 1) In utero and lactational PCB exposure increases bladder sensory afferent nerve fiber density coincident with increased voiding frequency in mice. 2) PCB disposition in the urine and bladder correlate with inflammation. 3) PCBs increase ATP and sensory afferent density by acting on the DRG neuronal cell body or peripheral axons in contact with the urothelium. 4) Purinergic receptors mediate PCB effects on sensory afferents in vitro and voiding dysfunction in vivo. This project will yield novel mechanistic data regarding not only the effect of developmental PCBs on voiding function, but also the role of purinergic signaling in mediating the effects of environment exposures that confer risk for LUTS. This information is urgently needed to inform rational strategies for minimizing LUTS risk by mitigating relevant exposures in susceptible populations and for identifying novel therapeutic targets. Findings from these studies will also further the development of mechanistically based screening platforms for identifying other environmental risk factors for LUTS. Equally important, this work will fill gaps in my training, which will allow me to realize my career goal of becoming an independent investigator.

下尿路症状（LUTS）影响所有年龄段的男性和女性，导致严重的医疗保健问题。 成本和生活质量下降。膀胱炎症是导致疼痛的LUTS的常见原因， 尿急和尿频增加。现有的治疗方法只能缓解症状;它们不能治疗 其根本基础。开发新的和更有效的方法来治疗或预防LUTS是必要的。 由于我们对泌尿功能是如何获得的以及为什么会恶化的理解不完全，而 环境因素与许多疾病的发病机制有关，无论它们是否决定了个体 LUTS的风险研究不足。这个项目的目标是测试新的机械假说， 发育PCB暴露通过炎症机制诱导嘌呤能信号传导，导致 传入神经活动增加和膀胱排尿功能障碍。多氯联苯是已知的中枢神经 系统神经毒物，但它们对周围神经系统的影响，这是关键涉及膀胱 功能，基本上是未知的。为了验证这一假设，我将小鼠暴露于母体中多氯联苯的混合物中， 整个妊娠期和哺乳期的饮食。多氯联苯混合物模拟了前12种多氯联苯同系物的比例 在加州的母亲血清中发现，这些母亲有可能生下神经发育障碍的孩子。 disorder.令人信服的初步证据暗示炎症和嘌呤能信号传导是一种机制， 早期接触多氯联苯会影响年轻人的泌尿功能。我建议在我之前的基础上 通过利用Lein博士和Bjorling博士的环境和专业知识来填补我的研究经验的空白 培训将有助于我成功完成以下具体目标，测试假设： 1)子宫内和哺乳期PCB暴露增加膀胱感觉传入神经纤维密度， 增加小鼠的排尿频率。2)多氯联苯在尿液和膀胱中的分布与炎症有关。第三章 多氯联苯通过作用于背根神经节神经元细胞体或外周轴突来增加ATP和感觉传入密度 与尿道接触4)嘌呤能受体介导PCB对感觉传入的影响 体内排尿功能障碍。该项目将产生新的机理数据，不仅涉及 发育PCB对排尿功能的影响，以及嘌呤能信号在介导 环境暴露会带来LUTS风险。我们迫切需要这些信息， 通过减轻易感人群的相关暴露来最大限度降低LUTS风险的策略， 确定新的治疗靶点。这些研究的结果也将进一步发展 以机械为基础的筛选平台，用于识别LUTS的其他环境风险因素。同样 重要的是，这项工作将填补我在培训中的空白，这将使我实现成为一名 独立调查员