PCB induced neurogenic inflammation mediates bladder dysfunction

点击翻译按钮获取中文摘要

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.