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

基本信息

批准号：
9763574
负责人：
Kimberly Preston Keil Stietz
金额：
$ 9.55万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2019-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763574
关键词：
Address Adult Adverse effects Affect Afferent Neurons Age Agonist Automobile Driving Axon Bladder Bladder Dysfunction California Child Communication Data Deterioration Development Developmental Biology Disease Environment Environmental Pollution Environmental Risk Factor Epithelial Cells Exposure to Female Frequencies Functional disorder Goals Health Care Costs Image In Vitro Incidence Individual Inflammation Inflammatory Knowledge Lactation Link Mediating Mentors Methods Microelectrodes Microfluidic Microchips Modeling Monitor Mothers Mus Nerve Fibers Neuraxis Neurobiology Neurodevelopmental Disorder Neurogenic Inflammation Neurons Neurotoxins Output Pain Parents Pathogenesis Peripheral Peripheral Nervous System Pharmacology Polychlorinated Biphenyls Population 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 awake base 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 prevent prophylactic screening success two-photon urinary young adult

项目摘要

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，导致重大的医疗保健问题成本和生活质量下降。膀胱炎症是 LUTS 的常见原因，会导致疼痛、排尿的紧迫性和频率增加。现有疗法只能缓解症状；他们不治疗他们的根本基础。开发新的、更有效的方法来治疗或预防 LUTS 是由于我们对泌尿功能是如何获得以及为什么会恶化的不完全了解，这阻碍了我们的研究。尽管环境因素与许多疾病的发病机制有关，无论它们是否决定个体 LUTS 的风险尚未得到充分研究。该项目的目标是测试新的机制假设发育过程中的 PCB 暴露会通过炎症机制诱导嘌呤能信号传导，从而导致传入神经活动增加和膀胱排尿功能障碍。 PCBs 已知是中枢神经系统神经毒物，但它们对周围神经系统的影响，该系统与膀胱密切相关的功能，很大程度上是未知的。为了验证这个假设，我将小鼠暴露在母体内的 PCB 混合物中。整个妊娠期和哺乳期的饮食。 PCB 混合模仿了前 12 种 PCB 同系物的比例在加利福尼亚州一些母亲的血清中发现了这种物质，这些母亲有可能生下患有神经发育障碍的孩子紊乱。令人信服的初步证据表明炎症和嘌呤能信号传导是一种机制生命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空白培训将有助于我成功完成以下具体目标，测试假设： 1) 在子宫内和哺乳期接触 PCB 会增加膀胱感觉传入神经纤维密度，这与小鼠的排尿频率增加。 2) PCB在尿液和膀胱中的分布与炎症相关。 3） PCB 通过作用于 DRG 神经元细胞体或外周轴突来增加 ATP 和感觉传入密度与尿路上皮接触。 4) 嘌呤能受体介导 PCB 对体外感觉传入的影响体内排尿功能障碍。该项目将产生新颖的机械数据，不仅涉及发育性多氯联苯对排尿功能的影响，以及嘌呤能信号在介导排尿功能中的作用环境暴露会带来 LUTS 风险。迫切需要这些信息来告知理性通过减少易感人群的相关暴露来最小化 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推动基于机械的筛选平台，用于识别 LUTS 的其他环境风险因素。同样重要的是，这项工作将填补我的培训空白，这将使我实现成为一名独立调查员。