The role of amphiregulin in mediating radiation cystitis in cancer survivors

双调蛋白在介导癌症幸存者放射性膀胱炎中的作用

• 批准号: 10636699
• 负责人: Bernadette Margaretha Maria Zwaans
• 金额: $ 43.92万
• 依托单位: WILLIAM BEAUMONT HOSPITAL RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636699
• 关键词: Acceleration; Acute; Acute Renal Failure with Renal Papillary Necrosis; Age; Aging; Amphiregulin; Animal Model; Applications Grants; Award; Benign; Binding; Biological Assay; Biological Markers; Bladder; Bladder Urothelium; Blood Vessels; Blood coagulation; Cancer Survivor; Cancer Survivorship; Cell Aging; Cell Line; Cells; Characteristics; Chronic; Chronic Kidney Failure; Collection; Colorectal Cancer; Doctor of Philosophy; Early Diagnosis; Environment; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Family; Fibrosis; Health; Heart; Hematuria; Hour; Human; In Vitro; Increased frequency of micturition; Injury; Injury to Kidney; Kidney; Knock-out; Knowledge; Life; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of prostate; Measures; Mediating; Medical; Microscopic; Mission; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Newly Diagnosed; Outcome; Outcome Study; Pain; Pathologic; Patients; Pattern; Pelvic Cancer; Pelvic Pain; Pelvis; Phase; Phenotype; Pilot Projects; Population; Pre-Clinical Model; Price; Process; Productivity; Profibrotic signal; Proteins; Proteomics; Quality of life; Radiation; Radiation Fibrosis; Radiation Injuries; Radiation therapy; Research; Research Institute; Risk; Risk Factors; Role; Sampling; Severities; Skin; Symptoms; Testing; Time; Tissues; Training; UPK2 gene; United States; Urination; Urine; Urothelial Cell; Urothelium; body system; cancer radiation therapy; cancer survival; cancer therapy; cell type; conventional therapy; detrusor muscle; effective therapy; experience; falls; improved; in vivo; innovation; irradiation; kidney fibrosis; member; overexpression; pre-clinical; predictive marker; prevent; radiation cystitis; response; senescence; side effect; survivorship; therapeutic target; tissue injury; tissue regeneration; tool; urinary

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.

摘要 癌症幸存者在美国是一个不断增长的人口，尽管他们中的许多人付出了沉重的代价， 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 盆腔癌的放射治疗RC是一种衰弱和进行性膀胱疾病， 有效的治疗可能会危及生命。因此，杀死癌症的治疗，最终可能会杀死 也是癌症幸存者癌症存活率的研究是非常重要的， 未满足的需求这项拨款提案具有很大的创新性，我们的研究结果可能会导致新的 放射性膀胱炎的诊断和治疗。 PI，Bernadette Zwaans博士，完成了成功和富有成效的NIDDK K 01培训奖。的 KO 1专注于使用SARRP更好地了解放射性膀胱炎的系统研究， 博蒙研究所的能力和资源丰富的环境。我们开发了一个RC 密切模拟人类状况的临床前模型。在这个模型中，我们发现RC是一个双相的 条件，其特征在于放射治疗后数周内的尿路上皮损伤（=急性RC）， 放射治疗后数月至数年内出现慢性纤维化、血管损伤和逼尿肌丧失（= 慢性RC）。我们已经确定双调蛋白（AREG）在放射治疗后显著升高， 并随着时间的推移继续大量增长。AREG是表皮生长因子家族的成员 EGF受体。它涉及许多过程，包括组织再生， 癌症、组织纤维化和细胞衰老。AREG存在于整个身体，但最 在膀胱尿道突出表达。我们假设AREG介导辐射诱导的 膀胱纤维化，可以作为潜在的治疗靶点。我们进一步假设AREG 可以作为预测性尿液生物标志物，以识别处于慢性疾病风险中的患者， RC. 我们的假设将通过三个具体目标进行测试：1。确定AREG的表达模式 以及其在维持正常和辐照膀胱中的尿路上皮完整性中的重要性; 2.确定角色 AREG介导辐射诱导的纤维化; 3.评估AREG作为RC的预测生物标志物。给定 凭借我们在RC临床前模型方面的经验，我们的团队非常适合成功完成这些目标。 这项研究正在调查RC的第一个潜在治疗靶点及其作为预测尿液的用途 生物标记物。我们的研究成果可以显著改善许多癌症患者的生活质量。 由于放射治疗而遭受严重膀胱并发症的幸存者。因此，本研究福尔斯属于 NIDDK改善癌症幸存者健康和生活质量的使命声明。

项目成果

Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing.

放射性膀胱炎分子机制的鉴定：RNA 测序的见解。

• DOI: 10.3390/ijms25052632
• 发表时间: 2024
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Mota,Sabrina;Ward,ElijahP;Bartolone,SarahN;Chancellor,MichaelB;Zwaans,BernadetteMM
• 通讯作者: Zwaans,BernadetteMM