Novel Mechanistic Approaches in Prevention, Treatment and Non-Invasive Assessment of Radiation Cystitis in Mice

预防、治疗和非侵入性评估小鼠放射性膀胱炎的新机制方法

基本信息

批准号：
10209635
负责人：
Anthony John Kanai
金额：
$ 44.35万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10209635
关键词：
Abdomen Acute American Cancer Society Antioxidants Apoptosis Biopsy Bladder Cancer Patient Cells Cessation of life Chronic Chronic Phase Clinical Collagen Complement Contrast Media Cystectomy Cystitis Data Deposition Diagnosis Dose Dyes Electrocoagulation Fibrosis Fluorescent Dyes Formalin Free Radical Scavengers Functional disorder Goals Hemorrhage Histologic Human Hyperbaric Oxygen Impairment In Situ Individual Inflammation Inflammatory Inner mitochondrial membrane Knockout Mice Lead Legal patent Magnetic Resonance Imaging Malignant Neoplasms Mitochondria Molecular Monitor Mus Myofibroblast NADP NGFR Protein Nerve Nerve Degeneration Organ Outcome Pathology Pelvic Cancer Pelvis Phase Physiological Pre-Clinical Model Prevention Radiation therapy Reactive Oxygen Species Reporter Rodent Safety Signal Transduction Smooth Muscle Soluble Guanylate Cyclase Telemetry Testing Therapeutic Agents Thinness Transforming Growth Factor beta Treatment Protocols United States Urothelial Cell Urothelium Visualization Woman afferent nerve awake cancer diagnosis clinically relevant conditional knockout cytochrome b5 reductase design ferumoxytol gadobutrol imaging modality intravesical irradiation men mitochondrial dysfunction mouse model non-invasive monitor novel novel therapeutics prevent radiation cystitis tumor urologic

项目摘要

ABSTRACT Pelvic organ tumors in men and women are projected to account for 40% and 18%, respectively, of new cancers diagnosed, and 31% and 26%, respectively, of cancer related deaths in the United States in 2020, according to the American Cancer Society’s Cancer Facts & Figures 2020. While nearly half of all pelvic cancer patients receive radiation therapy, the dose is limited and fractionated over weeks due to the potential for developing radiation cystitis. This is a debilitating secondary condition that can lead to disruption of the urothelium, inflammation, neurogenic detrusor overactivity (NDO), hemorrhagic cystitis and chronic fibrosis that may require a cystectomy. Current therapies such as cystoscopic fulguration, intravesical formalin and hyperbaric oxygen are often ineffective and focus on restricting hemorrhage rather than urological consequences. Thus, there is a critical need for preclinical models to better understand the pathophysiology of radiation cystitis, design novel mechanistic approaches in its prevention and treatment and non-invasive monitoring of these outcomes using clinically viable imaging methods. In our mouse models, bladders are either externalized or instilled with an infrared dye for selective irradiation (10Gy; 1Gy=100rad) to cause radiation cystitis with an acute phase (1- 3days) characterized by urothelial cell (UC) apoptosis and disruption of barrier function, and a chronic phase (8wks) with inflammation, afferent sensitization, NDO, and eventually collagen deposition, fibrosis and decreased bladder wall compliance. We propose to test mechanistically different classes of therapeutic and contrast agents for which we have strong preliminary data: 1) Mitochondrial targeted free radical scavenger, XJB-5-131, to decrease reactive oxygen species that inhibit mitophagy; 2) p75 neurotrophin receptor (p75NTR) modulator, LM11A-31, to decrease urothelial cell apoptosis and barrier disruption; 3) soluble guanylyl cyclase (sGC) activator, cinaciguat, to decrease inflammation, afferent sensitization and collagen deposition to treat NDO and fibrosis; and 4) intravesical infrared dye and novel contrast media mixture, gadobutrol/ferumoxytol, to selectively irradiate the bladder within the abdomen and to enhance the capabilities of magnetic resonance imaging (MRI) for non-invasive assessment of fibrosis in the bladder wall, respectively. As LM11A-31 and cinaciguat have passed phase 1 clinical safety trials for non-urological pathologies, they have considerable clinical relevance in the prevention and treatment of radiation cystitis. The overall goals of the proposal are to better characterize the pathophysiology of radiation cystitis and to design clinically relevant treatment protocols utilizing the proposed agents individually or in combination. Progress toward this goal will be monitored using decerebrate or awake (telemetric) cystometrogram (CMG) recordings, MRI, histological and molecular approaches, mitophagy reporter (mt-keima) mice, and conditional knockout mice for NADPH cytochrome b5 reductase 3 (CyB5R3) in smooth muscle or nerves which renders sGC unresponsive to NO• in these cells.

抽象的男性和女性盆腔器官肿瘤预计分别占新发癌症的 40% 和 18% 据统计，2020 年美国癌症相关死亡人数分别占 31% 和 26% 美国癌症协会 2020 年癌症事实与数据。虽然近一半的盆腔癌患者接受放射治疗时，剂量受到限制，并在数周内分次进行，因为有可能发生放射性膀胱炎是一种使人衰弱的继发性疾病，可导致尿路上皮破坏，炎症、神经源性逼尿肌过度活动（NDO）、出血性膀胱炎和慢性纤维化，可能需要目前的治疗方法包括膀胱镜电灼术、膀胱内福尔马林和高压氧治疗。往往无效，并且侧重于限制出血而不是泌尿系统后果。迫切需要临床前模型来更好地了解放射性膀胱炎的病理生理学，设计新颖预防和治疗的机械方法以及对这些结果的非侵入性监测在我们的小鼠模型中，膀胱要么被外部化，要么被注入一种临床上可行的成像方法。用于选择性照射的红外染料（10Gy；1Gy=100rad）引起急性期放射性膀胱炎（1- 3 天）以尿路上皮细胞 (UC) 凋亡和屏障功能破坏为特征，以及慢性期（8 周）伴有炎症、传入敏化、NDO，以及最终的胶原沉积、纤维化和我们建议从机制上测试不同类别的治疗和治疗方法。我们拥有强有力的初步数据的造影剂：1) 线粒体靶向自由基清除剂， XJB-5-131，减少抑制线粒体自噬的活性氧；2) p75 神经营养素受体 (p75NTR) 调节剂 LM11A-31，减少尿路上皮细胞凋亡和屏障破坏；3) 可溶性鸟苷酸环化酶； (sGC) 激活剂 cinaciguat，可减少炎症、传入敏化和胶原蛋白沉积，从而治疗 NDO 和纤维化；和4)膀胱内红外染料和新型造影剂混合物，钆布醇/ferumoxytol，以选择性照射腹部膀胱并增强磁共振能力成像（MRI）分别用于膀胱壁纤维化的无创评估，如 LM11A-31 和 cinaciguat 已通过非泌尿病理学的 1 期临床安全性试验，具有相当大的该提案的总体目标是预防和治疗放射性膀胱炎的临床相关性。更好地表征放射性膀胱炎的病理生理学并设计临床相关的治疗方案将使用单独或组合使用所提议的药物来监控实现这一目标的进展。去大脑或清醒（遥测）膀胱内压描记图 (CMG) 记录、MRI、组织学和分子学 NADPH 细胞色素 b5 的方法、线粒体自噬报告基因 (mt-keima) 小鼠和条件敲除小鼠平滑肌或神经中的还原酶 3 (CyB5R3) 使 sGC 对这些细胞中的 NO• 无反应。