Cellular and molecular mediators of fibrosis in the development of urinary tract dysfunction

项目总结 临床治疗泌尿系疾病每年花费美国人超过40亿美元，要求 更好地了解这些疾病背后的或促成这些疾病的风险因素。我们提供令人信服的 一种新范式的证据表明，男人的胎儿和新生儿环境决定了他患上癌症的风险 成人良性前列腺疾病的泌尿系并发症。拟议的研究提供了必要的洞察力 良性前列腺疾病的发病机制、发病率及部分男性出现尿路并发症的原因 年龄较小或症状较重的前列腺增生症(BPH)。我们的初步结果显示 宫内和哺乳期(IUL)接触2，3，7，8四氯二苯并对二恶英(TCDD)导致严重尿液 易患良性前列腺增生症的小鼠的功能障碍。TCDD是一种广泛存在于美国人血清中的污染物 男性，以及芳烃受体(AHR)的选择性激活剂，AHR是一种可以被 许多持久性有机污染物。我们分离了IUL TCDD暴露的两种潜在机制 损害尿路功能：在下尿路发育过程中增加感觉神经纤维 增强雌激素受体信号。我们还发现，接触TCDD时小鼠的年龄 测定对小鼠排尿功能的影响。成人接触TCDD的影响与IUL相反 暴露-它保护易患BPH泌尿系统并发症的小鼠的排尿功能障碍。这些 这些发现创造了一个极好的机会来测试前列腺和下尿路中AHR的激活 对排尿功能障碍有治疗作用。我们合成了新型的选择性AHR调制器 (SAHRM)，在体外验证了它们的效力，并将在体内进行临床前测试。这份提案有三个 特定的目标将检验以下假设：(1)IUL TCDD暴露增加感觉数量 前列腺和前列腺尿路中的神经纤维对排尿功能有持久的影响，(2)IUL TCDD 暴露通过一种需要间质雌激素受体-α(ERα)的机制损害尿路功能，以及 (3)接触TCDD对尿功能的影响因接触时间、围产期不同而异。 经期与成年期。作为目标3的一部分，我们还将测试成人接触SAHRM的假设， 它没有TCDD样的毒性，通过减少BPH易感性患者的排尿功能障碍而提供治疗益处 老鼠。通过建立接触TCDD和排尿功能之间的机械联系，建议 研究启动了对一种疾病过程的原创性研究，这一过程以前从未与发育起源或 AHR信令。我们还期望揭示AHR作为治疗泌尿系并发症的新靶点。 目前的药物对一种疾病--良性前列腺增生症--只有微弱的疗效。

PROJECT SUMMARY Clinical management of urinary disorders costs Americans over four billion dollars annually, demanding a better understanding of risk factors that underlie or contribute to these disorders. We provide compelling evidence for a new paradigm that a man's fetal andneonatal environment determines his risk of developing urinary complications of benign prostatic disease in adulthood. The proposed studies offer needed insight into disease pathogenesis, incidence, and why some men develop urinary complications of benign prostate hyperplasia (BPH) at a younger age or with more severe symptoms than others. Our preliminary results show in utero and lactational (IUL) exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) causes severe urinary dysfunction in mice susceptible to BPH. TCDD is a widespread contaminant, ubiquitous in serum of American men, and a selective activator of the aryl hydrocarbon receptor (AHR), a receptor that can be activated by many persistent organic pollutants. We isolated two potential mechanisms by which IUL TCDD exposure impairs urinary function: by increasing sensory nerve fibers during lower urinary tract development and by enhancing estrogen receptor signaling. We also discovered that age of mice at the time of TCDD exposure determines the impact on mouse urinary function. Adult TCDD exposure has the opposite effect of IUL exposure - it protects against urinary dysfunction in mice susceptible to urinary complications of BPH. These findings create a remarkable opportunity to test whether AHR activation in the prostate and lower urinary tract of adult males is therapeutic for urinary dysfunction. We synthesized novel selective AHR modulators (SAHRMs), verified their potency in vitro, and will perform pre-clinical testing in vivo. This proposal's three specific aims will test the following hypotheses: (1) IUL TCDD exposure increases the number of sensory nerve fibers in the prostate and prostatic urethra, having a lasting effect on urinary function, (2) IUL TCDD exposure impairs urinary function through a mechanism requiring stromal estrogen receptor-alpha (ERα), and (3) the impact of TCDD exposure on urinary function differs depending on when exposure occurs, perinatal period versus adulthood. As part of aim 3, we will also test the hypothesis that adult exposure to SAHRMs, which lack TCDD-like toxicity, offers therapeutic benefit by reducing urinary dysfunction in BPH susceptible mice. By establishing a mechanistic connection between TCDD exposure and urinary function, the proposed studies launch original lines of research into a disease process never before linked to developmental origins or AHR signaling. We also expect to reveal the AHR as a new therapeutic target for treating urinary complications of BPH, a disease against which current drugs are only marginally effective.