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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的癌症幸存者在美国的人口增长，尽管其中许多人付出了沉重的代价由于癌症疗法的长期副作用，他们的生存状况。辐射膀胱炎（RC）结果从骨盆癌的放射治疗。 RC是一种令人衰弱和渐进的膀胱状态，没有有效的疗法可能会威胁生命。因此，杀死癌症的治疗方法可能最终杀死癌症幸存者也是如此。癌症生存研究的研究非常重要，代表了很大的未满足的需求。该赠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诊断和治疗辐射膀胱炎。 PI，Bernadette Zwaans博士获得了一项成功且富有成效的NIDDK K01培训奖。这 KO1专注于对使用SARRP更好地理解辐射膀胱炎的系统研究 Beaumont研究所的能力且足智多谋的环境。我们开发了RC 紧密模仿人类状况的临床前模型。在此模型中，我们确定RC是双相病情，以尿路疗法后的几周（=急性RC）和放射治疗后的几个月至数年，慢性纤维化，血管损伤和迫切肌肉的丧失（= 慢性RC）。我们已经确定放射治疗后的两次两极蛋白（AREG）显着升高随着时间的流逝，继续增长。 AREG是表皮生长因子家族的成员结合EGF受体。它与许多过程有关，包括组织再生，癌症，组织纤维化和细胞衰老。 AREG在整个身体中都存在，但最多在膀胱尿铺上明显表达。我们假设AREG介导了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 可以用作预测性尿液生物标志物，以识别有慢性慢性风险的患者 RC。我们的假设将通过三个特定目的进行检验：1。确定AREG的表达模式以及它在维持正常和辐照膀胱中尿路上皮完整性方面的重要性； 2。确定角色 AREG在介导辐射诱导的纤维化中； 3。评估AREG作为RC的预测生物标志物。给出我们在RC临床前模型的经验非常适合成功完成这些目标。这项研究正在研究RC的第一个潜在治疗靶点及其用作预测性尿液生物标志物。我们研究的结果可以显着改善许多癌症的生活质量由于放射治疗而患有严重膀胱并发症的幸存者。因此，这项研究属于 NIDDK的任务陈述，以改善癌症幸存者的健康和生活质量。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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