PCB induced neurogenic inflammation mediates bladder dysfunction

下尿路症状(LUT)影响所有年龄段的男性和女性，导致重大医疗保健 成本和生活质量的降低。膀胱炎是LUTS的常见原因，它会导致疼痛， 排尿的紧迫性和频度增加。现有的治疗方法只是轻微的症状；它们不能治疗 它们的根本基础。治疗或预防LUTS的新的和更有效的方法的发展是 受阻于我们对尿液功能是如何获得的以及为什么会恶化的不完全理解。而当 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 对LUTS的风险研究不足。这个项目的目标是测试新的机械假说 发育中的多氯联苯暴露通过炎症机制诱导嘌呤能信号转导，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，这与膀胱密切相关 功能，在很大程度上是未知的。为了验证这一假设，我将让小鼠接触母体体内的多氯联苯混合物 在整个孕期和哺乳期的饮食。印刷电路板的混合模仿了排名前12位的印刷电路板同类产品的比例 在加州母亲的血清中发现，这些母亲有生下神经发育不良孩子的风险 无序。令人信服的初步证据表明炎症和嘌呤能信号转导是一种机制 早年接触多氯联苯会影响年轻人的尿路功能。我建议在我以前的基础上再接再厉 利用Lein博士和Bjorling博士的环境和专业知识来填补我的 培训将有助于我成功地完成以下具体目标，以检验以下假设： 1)宫内和哺乳期接触多氯联苯可增加膀胱感觉神经纤维密度，与 增加小鼠排尿频率。2)多氯联苯在尿液和膀胱中的分布与炎症有关。3) 多氯联苯通过作用于背根神经节神经元胞体或外周轴突增加三磷酸腺苷和感觉传入密度 与尿路上皮接触。4)嘌呤能受体在体外介导多氯联苯对感觉神经传入的影响 体内排尿功能障碍。该项目将产生新的机械数据，不仅涉及到 发育过程中多氯联苯对排尿功能的影响，也是嘌呤能信号调节作用的基础。 环境暴露会给LUT带来风险。迫切需要这些信息来通知Rational 通过减少易感人群的相关暴露来最小化LUTS风险的战略 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，这份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。

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.