Contribution of obesity-environment interaction in bladder dysfunction

肥胖与环境相互作用对膀胱功能障碍的影响

• 批准号: 10594037
• 负责人: Kimberly Preston Keil Stietz
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-17 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10594037
• 关键词: Adult; Adverse effects; Anesthesia procedures; Biological Assay; Bladder; Bladder Dysfunction; Bone Marrow; Child; Clinical Trials; Data; Development; Disease; Disease Progression; Environment; Etiology; Exposure to; Female; Frequencies; Functional disorder; Future; Healthcare; Heterogeneity; Heterozygote; High Fat Diet; Homozygote; Human; Immunohistochemistry; Incontinence; Infiltration; Inflammation; Inflammation Mediators; Intervention; Laboratories; Lactation; Lead; Life; Link; Macrophage; Mediating; Mus; Obesity; Organ; Outcome; Overactive Bladder; Pathway interactions; Patients; Polychlorinated Biphenyls; Population; Pregnancy; Quality of life; Risk Factors; Rodent; Role; Severities; Spottings; Symptoms; Testing; Therapeutic; Therapeutic Agents; Toxic Environmental Substances; Urination; Urine; Visualization; Woman; care burden; clinically relevant; diet-induced obesity; effective therapy; environmental chemical; experience; immune cell infiltrate; lower urinary tract symptoms; men; monocyte; mouse development; mouse model; novel; offspring; prevent; red fluorescent protein; stressor; urinary; weight loss intervention; young adult

Lower urinary tract symptoms (LUTS) such as urgency and frequent urination (overactive bladder) impose a significant healthcare burden and reduce quality of life. Factors which contribute to onset and severity of symptoms are not completely understood but are likely multifactorial, therefore we propose to lead new efforts in understanding interactions which may contribute to LUTS. In other organs, developmental exposures to environmental toxicants alone or in combination with a second stressor can influence disease progression later in life. Obesity is also a risk factor for many diseases including overactive bladder. Whether an obesity-environmental interaction paradigm exists for LUTS is unknown but could be a new risk factor for urinary disease. Here we propose to test the hypothesis that developmental exposure to polychlorinated biphenyls (PCBs) exacerbates urinary dysfunction when mice are later challenged with a common second stressor, diet induced obesity. Our preliminary data indicate that developmental exposure to environmental toxicants, polychlorinated biphenyls (PCBs), in mice, leads to small, more frequent voids as young adults. Other studies have shown that obesity is linked to bladder dysfunction, with high fat diets linked to small more frequent voids in rodents. Preliminary data indicate that developmental exposure to PCBs or a high fat diet alone increase F4/80+ macrophages in female bladder. Our expected results are that combined exposure to PCBs and high fat diet together will exacerbate increased voiding frequency. We also hypothesize that bladder inflammation, specifically increased macrophages, are a convergent target for both hits thus expected results are that combined exposure will lead to increased number of macrophages in bladder compared to either hit alone. Whether macrophages are the major inflammatory mediator and whether elevated macrophage numbers result from bladder resident macrophages or infiltrating monocytes which differentiate into macrophages is unknown but of potential clinical relevance since therapeutic approaches to block infiltrating monocytes could be employed. We will test our hypothesis in three aims. The first testing whether developmental PCB exposure combined with a high fat diet in adulthood increases voiding frequency and decreases voided urine volume in mice compared to either stressor alone. The second testing whether developmental PCB exposure combined with a high fat diet exacerbates bladder inflammation by increasing the abundance of infiltrating monocytes which differentiate into macrophages. The third testing whether infiltrating monocytes contribute to PCB or high fat diet induced voiding dysfunction.

下尿路症状（LUTS），如尿急和尿频（膀胱过度活动症） 造成了巨大医疗负担并降低了生活质量。导致发病的因素 症状的严重程度还不完全清楚，但可能是多因素的，因此我们 建议在理解可能有助于LUTS的相互作用方面做出新的努力。换句 器官，发育暴露于环境毒物单独或结合 第二个压力源可以影响以后生活中的疾病进展。肥胖也是一个危险因素， 包括膀胱过度活动症在内的多种疾病。肥胖与环境的相互作用 目前还不清楚LUTS的存在模式，但可能是泌尿系统疾病的一个新的风险因素。这里我们 建议测试的假设，发展接触多氯联苯（PCBs） 当小鼠随后用共同的第二应激源攻击时加剧了泌尿功能障碍， 饮食引起的肥胖。我们的初步数据表明， 有毒物质，多氯联苯（PCB），在小鼠中，导致小，更频繁的空隙作为年轻 成年人了其他研究表明，肥胖与膀胱功能障碍有关，高脂肪饮食 与啮齿类动物更频繁的小空隙有关。初步数据表明，发育 暴露于多氯联苯或高脂肪饮食单独增加F4/80+巨噬细胞在女性膀胱。我们 预期的结果是，多氯联苯和高脂肪饮食的联合暴露将加剧 增加排尿频率。我们还假设膀胱炎症，特别是 增加的巨噬细胞是两种命中的会聚靶标，因此预期结果是， 联合暴露将导致膀胱中巨噬细胞数量增加， 一个人打。巨噬细胞是否是主要的炎症介质， 巨噬细胞数量来自膀胱驻留巨噬细胞或浸润单核细胞， 分化为巨噬细胞的可能性尚不清楚，但由于治疗性 可以采用阻断浸润单核细胞的方法。我们将在三个方面来检验我们的假设 目标。第一次测试是否发育PCB暴露结合高脂肪饮食， 成年小鼠的排尿频率增加，排尿量减少， 或者单独的压力源。第二个测试是， 高脂肪饮食通过增加浸润性炎症细胞的丰度而加剧膀胱炎症。 单核细胞分化成巨噬细胞。第三次测试是否浸润单核细胞 有助于PCB或高脂肪饮食引起的排尿功能障碍。