The role of amphiregulin in mediating radiation cystitis in cancer survivors

摘要 癌症幸存者是美国不断增长的人口，尽管他们中的许多人为癌症付出了沉重的代价 由于癌症治疗的长期副作用，他们的生存状况。放射性膀胱炎(RC)结果 从骨盆癌放射治疗中脱颖而出。RC是一种衰弱和进行性的膀胱疾病，没有 可能危及生命的有效疗法。因此，杀死癌症的治疗方法可能最终会杀死 癌症幸存者也是如此。癌症存活率的研究具有非常重要的意义，代表着一种伟大的 未得到满足的需求。这项拨款建议极具创新性，我们的研究结果可能会带来新的 放射性膀胱炎的诊断和治疗。 这位PI，Bernadette Zwaans博士，成功地完成了NIDDK K01培训奖。这个 KO1专注于使用SARRP更好地了解放射性膀胱炎的系统研究，网址为 博蒙特研究所的能干和足智多谋的环境。我们开发了一款RC 临床前模型，非常接近人类的情况。在这个模型中，我们发现RC是一个双相的 状况，以放射治疗后几周的尿路上皮损伤为特征(=急性RC)，以及 放射治疗后数月至数年的慢性纤维化、血管损伤和逼尿肌丧失(= 慢性RC)。我们已经发现，在放射治疗后，两性调节蛋白(AREG)显著升高， 并随着时间的推移继续丰富增长。AREG是表皮生长因子家族的成员 它结合了EGF受体。它参与了许多过程，包括组织再生， 癌症、组织纤维化和细胞衰老。AREG存在于全身，但大多数 在膀胱尿路上皮细胞中有显著表达。我们假设AREG介导辐射诱导 膀胱纤维化，可作为潜在的治疗靶点。我们进一步假设AREG 可作为预测尿液生物标志物，以识别有患慢性病风险的患者 RC. 我们的假设将通过三个具体的目标来验证：1.确定AREG的表达模式 以及在正常和照射后的膀胱中维持尿路上皮完整性的重要性；2.确定其作用 AREG在介导辐射诱导的纤维化中的作用；3.评估AREG作为RC的预测生物标志物。vt.给出 根据我们在RC临床前模型方面的经验，我们的团队非常适合成功实现这些目标。 这项研究正在调查RC的第一个潜在治疗靶点及其作为尿液预测指标的用途。 生物标志物。我们的研究结果可以显著改善许多癌症患者的生活质量 因放射治疗而出现严重膀胱并发症的幸存者。因此，这项研究属于 NIDDK的使命宣言是改善癌症幸存者的健康和生活质量。

ABSTRACT Cancer survivors are a growing population in the United States, though many of them pay a heavy price for their survivorship status due to long-term side effects from cancer therapies. Radiation cystitis (RC) results from radiation therapy for pelvic cancers. RC is a debilitating and progressive bladder condition with no effective therapy that may be life-threatening. Thus, the treatment that killed the cancer, may ultimately kill the cancer survivor as well. Research in cancer survivorship is highly significant and represent a great unmet need. This grant proposal is greatly innovative and results from our studies may lead to new diagnosis and treatment for radiation cystitis. The PI, Bernadette Zwaans, PhD, completed a successful and productive NIDDK K01 training award. The KO1 was focused on a systematic research on better understanding of radiation cystitis using SARRP at the capable and resourceful environment at Beaumont Research Institute. We developed an RC preclinical model that closely mimics the human condition. In this model, we identified that RC is a biphasic condition, characterized by urothelial damage in the weeks after radiation therapy (=acute RC), and by chronic fibrosis, vascular damage, and loss of detrusor muscle in months to years after radiation therapy (= chronic RC). We have identified Amphiregulin (AREG) to be significantly elevated after radiation therapy, and to continue to grow in abundance over time. AREG is a member of the epidermal growth factor family that binds the EGF receptor. It has been implicated in many processes including tissue regeneration, cancer, tissue fibrosis, and cellular senescence. AREG is present throughout the body but is most prominently expressed in the bladder urothelium. We hypothesize that AREG mediates radiation-induced bladder fibrosis and can serve as a potential therapeutic target. We further hypothesize that AREG can serve as a predictive urine biomarker to identify patients that are at risk for developing chronic RC. Our hypothesis will be tested through three specific aims: 1. Determine the expression pattern of AREG and its importance in maintaining urothelial integrity in normal and irradiated bladder; 2. Determine the role of AREG in mediating radiation-induced fibrosis; 3. Assess AREG as a predictive biomarker for RC. Given our experience with RC preclinical models our team is well-suited to successfully complete these aims. This study is investigating the first potential therapeutic target for RC and its use as a predictive urine biomarker. The outcomes of our studies can significantly improve the quality of life of many cancer survivors suffering from severe bladder complications due to radiation therapy. Thus, this study falls within the mission statement of the NIDDK to improve health and quality of life of cancer survivors.