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

尿路功能障碍发展过程中纤维化的细胞和分子介质

• 批准号: 10295668
• 负责人: RICHARD Eugene PETERSON
• 金额: $ 5.08万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295668
• 关键词: Address; Adult; Age; Aging; American; Animal Model; Aryl Hydrocarbon Receptor; Benign; Benign Prostatic Hypertrophy; COL1A1 gene; Cell physiology; Cells; Clinical; Clinical Management; Collagen; Deposition; Development; Dioxins; Disease; Disease model; Endocrine Disruptors; Environment; Environmental Exposure; Estrogen Receptor alpha; Estrogen Receptors; Estrogen receptor positive; Estrogens; Exposure to; Fibroblasts; Fibrosis; Functional disorder; Future; Gene Expression; Goals; Health; Health Care Costs; Hormones; Human; Image; Impairment; In Vitro; Incidence; Increased frequency of micturition; Lactation; Link; Longevity; Lower urinary tract; Mediator of activation protein; Medical; Methods; Modeling; Molecular; Molecular Target; Mus; Myofibroblast; Neonatal; Nerve Fibers; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Preclinical Testing; Prevention; Process; Prostate; Prostatic; Prostatic Diseases; Prostatic Urethra; Raloxifene; Receptor Activation; Receptor Signaling; Regulation; Research; Risk; Risk Factors; Role; Selective Estrogen Receptor Modulators; Serum; Smooth Muscle Myocytes; Symptoms; Testing; Tetrachlorodibenzodioxin; Therapeutic; Time; Tissues; Toxic Environmental Substances; Toxic effect; Urinary tract; Urology; afferent nerve; cell type; clinical practice; clinically relevant; cost; effective therapy; environmental chemical; experimental study; fetal; fetal dioxin exposure; improved; in utero; in vivo; in vivo evaluation; innovation; insight; lower urinary tract symptoms; male; man; men; molecular targeted therapies; mouse model; new therapeutic target; novel; novel therapeutics; parent grant; perinatal period; persistent organic pollutants; prenatal exposure; prevent; public health relevance; receptor; recombinase-mediated cassette exchange; therapeutic target; urinary; urologic

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.

项目摘要 泌尿系统疾病的临床管理每年花费美国人超过40亿美元， 更好地了解这些疾病背后或促成这些疾病的风险因素。我们提供令人信服的 一个新的范例的证据，一个人的胎儿和新生儿的环境决定了他的风险发展 成人期良性前列腺疾病的泌尿系统并发症。拟议的研究提供了必要的洞察力， 疾病的发病机制，发病率，以及为什么有些男性发展为良性前列腺泌尿系统并发症 前列腺增生（BPH）在年轻的时候或有更严重的症状比别人。我们的初步结果表明 子宫内和哺乳期（IUL）暴露于2，3，7，8-四氯二苯并-对-二恶英（TCDD）可导致严重的尿 BPH易感小鼠的功能障碍。TCDD是一种广泛存在的污染物，在美国人的血清中普遍存在， 和芳香烃受体（AHR）的选择性激活剂，芳香烃受体是一种可以被 许多持久性有机污染物。我们分离出两种可能的机制， 损害泌尿功能：在下尿路发育期间增加感觉神经纤维， 增强雌激素受体信号传导。我们还发现，小鼠在接触TCDD时的年龄 测定对小鼠泌尿功能的影响。成人TCDD暴露具有IUL相反的效果 暴露-它可以防止对BPH泌尿并发症敏感的小鼠的泌尿功能障碍。这些 这一发现创造了一个非凡的机会来测试AHR是否在前列腺和下尿路激活， 是治疗泌尿功能障碍的药物。我们合成了新型的选择性AHR调节剂， （SAHRMs），在体外验证其效力，并将在体内进行临床前试验。这个提议是三个 具体的目标将测试以下假设：（1）IUL TCDD暴露增加了感官的数量， 前列腺和前列腺尿道中的神经纤维，对排尿功能具有持久影响，（2）IUL TCDD 暴露通过需要基质雌激素受体α（ERα）的机制损害泌尿功能， (3)四氯二苯并对二恶英暴露对泌尿功能的影响因暴露发生时间、围产期 时期与成年期。作为目标3的一部分，我们还将检验成人暴露于SAHRM的假设， 缺乏TCDD样毒性，通过减少BPH易感者的泌尿功能障碍提供治疗益处。 小鼠通过建立TCDD暴露与泌尿功能之间的机制联系， 这些研究启动了对一种疾病过程的原创性研究，这种疾病过程以前从未与发育起源有关， AHR信号。我们还期望揭示AHR作为治疗泌尿系统并发症的新治疗靶点 前列腺增生症，目前的药物对这种疾病只有轻微的效果。