Endocrine disruption in the aging urothelium

描述(由申请人提供)：内分泌系统的改变在老龄化人口中得到了很好的证实。出现的情况包括糖尿病、甲状腺并发症、骨质疏松症、心血管事件和癌症。重金属，如砷，是已知的内分泌干扰物，通过饮用水长期接触与老龄化人口特有的一系列慢性病有关，包括膀胱癌。膀胱癌(BLCA)是一种老年疾病，平均诊断年龄为73岁。BLCA是所有实体肿瘤中复发率最高的肿瘤之一，其疗程对生活质量有显著影响。20%的患者在手术切除后乳头状肿瘤复发，需要经常监测。此外，肌肉浸润性疾病的患者在根治性膀胱切除术后7至8个月会出现盆腔复发。BLCA有一个病态的疾病过程，每年造成30亿美元的损失。此外，大多数死于BCA的患者都接受了最终失败的根治性治疗。对BCA的病理生理学缺乏了解，导致缺乏有效的治疗，也使制定预防措施最终促进健康老龄化变得困难。这一点值得考虑，因为在不到50年的时间里，超过25%的美国人口将超过65岁。BCa最常见的诱因是终生长期暴露于环境风险因素，如砷。砷调节糖皮质激素受体(GR)，这是一种类固醇激素激活的转录因子，在膀胱中具有保护作用。血管生成素样蛋白4(Angiopoietin-like 4，ANGPTL4)是膀胱中的一种保护性蛋白，受GR转录调控，并在砷暴露后下降。这项建议旨在研究内分泌紊乱如何导致尿路上皮改变，最终导致膀胱癌。我曾假设，GR介导的ANGPTL4反式激活的慢性失调扰乱了尿路上皮的正常生理过程。我将通过(1)确定砷暴露对ANGPTL4转录调控的影响，(2)评估砷暴露对GR反式激活的影响，以及(3)观察慢性砷暴露如何由于破坏GR对ANGPTL4的转录控制而促进细胞转化来解决这一假设。此外，我将评估年轻和老年小鼠组织中的GR和ANGPTL4，以验证我的发现结果。NIA的一个首要研究重点是确定与年龄相关的人类生理变化的特征。众所周知，老年人的内分泌系统会发生复杂的变化。这项研究首次探索了糖皮质激素对膀胱的影响。这些努力的发现将有助于 对膀胱癌发生的特征以及与内分泌系统改变有关的其他年龄相关疾病的了解，如糖尿病、免疫抑制以及神经和行为变化。

DESCRIPTION (provided by applicant): Alterations of the endocrine system are well established in the aging population. Conditions that arise include diabetes, thyroid complications, osteoporosis, cardiovascular events, and cancer. Heavy metals, such as arsenic, are known endocrine disruptors and chronic exposure through drinking water is linked to a broad range of chronic diseases characteristic to the aging population, including cancer of the urinary bladder. Bladder cancer (BlCa) is a disease of the aging population with an average age of diagnosis at 73 years. BlCa has one of the highest recurrence rates of all solid tumors and the treatment course has a significant effect on quality of life. 20 percent of patients have recurrence of papillary tumors following surgical removal and require frequent surveillance. Furthermore, patients with muscle invasive disease have pelvic recurrence seven to eight months after radical cystectomy. BlCa has a morbid disease process and costs the US 3 billion dollars per year. Furthermore, the majority of patients that lose their lives to BlCa have undergone curative treatment that ultimately fails. Poor understanding of the pathophysiology of BlCa contributes to the lack of effective treatment and also makes it difficult to develop preventative measures to ultimately promote healthy aging. This is important to consider because in less than 50 years, over 25 percent of the US population will be over the age of 65 years. BlCa is most commonly induced by chronic exposure to environmental risk factors throughout life, such as arsenic. Arsenic modulates glucocorticoid receptor (GR), a steroid hormone-activated transcription factor that is protective in the bladder. Angiopoietin-like 4 (ANGPTL4), a protective protein in the bladder, is transcriptionally regulated by GR and is decreased following arsenic exposure. This proposal aims to investigate how endocrine disruption contributes to changes in the urothelium that eventually lead to bladder cancer. I have hypothesized that chronic dysregulation of GR-mediated transactivation of ANGPTL4 disrupts normal physiological processes of the urothelium. I will address this hypothesis by (1) determining the effects of arsenic exposure on ANGPTL4 transcriptional regulation, (2) evaluating the effects of arsenic exposure on GR transactivation, and (3) observing how chronic arsenic exposure promotes cellular transformation due to disruption of GR transcriptional control of ANGPTL4. Further, I will evaluate GR and ANGPTL4 in tissues from young and old mice to validate the results of my findings. A top research priority at the NIA is to characterize age-related alterations in human physiology. It is well established that complex changes occur in the endocrine system of aging individuals. This study explores the effects of glucocorticoid disruption in the bladder for the first-time. Discoveries from these efforts will contribute to the characterization of bladder carcinogenesis as well as the understanding of other age-related conditions linked to alterations of the endocrine system, such as diabetes, immunosuppression, and neurological and behavioral changes.