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

基本信息

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
项目类别：
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

项目摘要

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)，例如尿急和尿频（膀胱过度活动症）造成重大的医疗负担并降低生活质量。导致发病的因素症状的严重程度尚未完全了解，但可能是多因素的，因此我们建议领导新的努力来理解可能有助于 LUTS 的相互作用。在其他方面器官、发育暴露于环境毒物单独或与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许多疾病，包括膀胱过度活动症。肥胖与环境是否相互作用 LUTS 是否存在范例尚不清楚，但可能是泌尿系统疾病的新危险因素。在这里我们提议检验以下假设：发育阶段接触多氯联苯 (PCB) 当小鼠随后受到常见的第二个压力源的挑战时，会加剧泌尿功能障碍，饮食引起的肥胖。我们的初步数据表明，发育暴露于环境有毒物质多氯联苯 (PCB) 会导致小鼠在年轻时出现小而频繁的排尿成年人。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排泄有关。初步数据表明，发育单独接触 PCB 或高脂肪饮食会增加女性膀胱中的 F4/80+ 巨噬细胞。我们的预期结果是，同时接触多氯联苯和高脂肪饮食会加剧排尿频率增加。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聚合目标，因此预期结果是与任一暴露相比，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炎症介质以及是否升高巨噬细胞数量来自膀胱驻留巨噬细胞或浸润单核细胞，分化为巨噬细胞尚不清楚，但具有潜在的临床意义，因为治疗可以采用阻止浸润单核细胞的方法。我们将分三步检验我们的假设目标。首次测试发育性 PCB 暴露与高脂肪饮食是否相结合与成年小鼠相比，成年小鼠的排尿频率增加，排尿量减少单独的压力源。第二次测试是否与开发 PCB 暴露相结合高脂肪饮食会增加浸润性炎症，从而加剧膀胱炎症单核细胞分化为巨噬细胞。第三次检测单核细胞是否浸润有助于PCB或高脂肪饮食引起的排尿功能障碍。