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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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，需要我们提供了令人信服的信息，以更好地了解这些疾病背后或导致这些疾病的风险因素。新范式的证据表明，男性的胎儿和新生儿环境决定了他的患病风险拟议的研究提供了对成年良性前列腺疾病的泌尿并发症的深入了解。疾病发病机制、发病率以及为什么一些男性会出现良性前列腺泌尿系统并发症我们的初步结果显示，前列腺肥大（BPH）发病年龄较轻，或症状较其他人严重。在子宫内和哺乳期 (IUL) 接触 2,3,7,8 四氯二苯并二恶英 (TCDD) 会导致严重的尿 TCDD 是一种广泛存在于美国人血清中的污染物。以及芳烃受体 (AHR) 的选择性激活剂，该受体可以通过我们分离出 IUL TCDD 暴露的两种潜在机制。损害泌尿功能：通过在下泌尿道发育期间增加感觉神经纤维以及通过我们还发现，暴露于 TCDD 时小鼠的年龄会增加。确定了成年TCDD暴露对小鼠泌尿功能的影响与IUL相反。暴露 - 它可以防止易患 BPH 泌尿并发症的小鼠的泌尿功能障碍。研究结果为测试 AHR 是否在前列腺和下尿路激活提供了绝佳的机会我们合成了新型选择性 AHR 调节剂。（SAHRM），在体外验证了它们的效力，并将在体内进行该提案的三个临床前测试。具体目标将检验以下假设： (1) IUL TCDD 暴露增加感觉数量前列腺和尿道前列腺部的神经纤维，对泌尿功能有持久影响，(2) IUL TCDD 暴露会通过一种需要基质雌激素受体-α (ERα) 的机制损害泌尿功能，并且 (3) TCDD暴露对泌尿功能的影响因暴露发生时间、围产期、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，可通过减少 BPH 易感性的泌尿功能障碍提供治疗益处通过建立 TCDD 暴露与泌尿功能之间的机制联系，建议研究启动了对疾病过程的原创研究，以前从未与发育起源或我们还期望揭示 AHR 作为治疗泌尿并发症的新治疗靶点。 BPH 是目前药物治疗效果有限的疾病。