Contribution of obesity-environment interaction in bladder dysfunction

下尿路症状(LUT)，如尿急和尿频(膀胱过度活动) 造成严重的医疗负担，降低生活质量。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的相互作用方面领导新的努力。在其他 器官，发育过程中单独暴露于环境毒物或与 第二个压力源可能会影响日后的疾病进展。肥胖也是一个危险因素 包括膀胱过度活动在内的许多疾病。肥胖是否与环境相互作用 LUTS的存在模式尚不清楚，但可能是泌尿系疾病的新危险因素。在这里我们 建议测试发育过程中暴露于多氯联苯(PCbs)的假设 当小鼠后来受到共同的第二应激源挑战时，会加剧排尿功能障碍， 饮食引起的肥胖。我们的初步数据表明，发育过程中暴露在环境中 在老鼠体内，有毒物质多氯联苯(PCBS)在幼年时会导致较小的、更频繁的排泄 成年人。其他研究表明，肥胖与高脂肪饮食下的膀胱功能障碍有关 与啮齿类动物的小而频繁的空洞有关。初步数据表明，发育 暴露于多氯联苯或高脂肪饮食本身就会增加女性膀胱中F4/80+巨噬细胞的数量。我们的 预期的结果是，暴露在多氯联苯和高脂肪饮食的共同作用将加剧 排尿频率增加。我们还假设膀胱炎，特别是 巨噬细胞增多，是两种命中的集中目标，因此预期结果是 联合暴露会导致膀胱中巨噬细胞数量的增加 单枪匹马。巨噬细胞是否是主要的炎症介质以及是否升高 巨噬细胞的数量是由膀胱内滞留的巨噬细胞或浸润性单核细胞引起的 分化为巨噬细胞尚不清楚，但自治疗以来具有潜在的临床意义 可以采用阻断浸润性单核细胞的方法。我们将在三年内检验我们的假设 目标。第一项测试表明，发育中的多氯联苯暴露与高脂肪饮食是否相结合 与小鼠相比，成年后小鼠排尿频率增加，尿量减少 要么是单独的压力源。第二个测试是发育期的印刷电路板暴露是否与 高脂肪饮食通过增加浸润性细胞的丰度而加剧膀胱炎 单核细胞分化为巨噬细胞。第三项检测是否渗入单核细胞 导致多氯联苯或高脂饮食导致排尿功能障碍。

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.