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.

抽象的预计男性和女性的骨盆器官肿瘤分别占新癌症的40％和18％据诊断为2020年美国与癌症相关的死亡分别为31％和26％美国癌症协会的癌症事实与图2020年。虽然几乎一半的骨盆癌患者接受放射疗法，由于有可能发展的潜力，剂量受到限制和分馏辐射膀胱炎。这是一种令人衰弱的次要条件，可能导致尿液中断，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膀胱切除术。当前的疗法，例如膀胱镜结合，遗内福尔马林和高压氧通常是无效的，专注于限制出血，而不是泌尿科后果。那有一个临床前模型的关键需求可以更好地了解辐射膀胱炎的病理生理学，设计新颖在预防和治疗以及对这些结果的预防和治疗和非侵入性监测方面的机械方法临床上可行的成像方法。在我们的鼠标模型中，膀胱要么是外部化或灌输的红外染料选择性辐射（10GY; 1GY = 100RAD）以急性相引起辐射膀胱炎（1- 3天）以尿路上皮细胞（UC）凋亡和屏障功能的破坏为特征，慢性期（8WK）带有炎症，传入的感觉，NDO，最终胶原蛋白沉积，纤维化和膀胱壁的依从性降低。我们建议测试机械不同类别的治疗性和我们拥有强大初步数据的对比剂：1）线粒体靶向自由基清除剂， XJB-5-131，以减少抑制线粒体的活性氧； 2）P75神经营养蛋白受体（P75NTR）调节剂LM11A-31，以减少尿路上皮细胞凋亡和屏障破坏； 3）可溶性瓜尼犬（SGC）激活剂Cinaciguat，以减少炎症，传入敏化和胶原蛋白沉积以治疗NDO 和纤维化； 4）静脉内红外染料和新型的对比培养基混合物gadobutrol/ferumoxytol，to 选择性地照射腹部内的膀胱并增强磁共振的能力成像（MRI）分别用于对膀胱壁中纤维化的非侵入性评估。如LM11A-31和 cinaciguat已通过了第1阶段的临床安全试验，用于非神经病理学，他们认为预防和治疗辐射膀胱炎的临床相关性。该提案的总体目标是更好地表征辐射膀胱炎的病理生理学并设计临床相关的治疗方案单独或组合使用拟议的代理。将使用杂交或清醒（遥测）膀胱图（CMG）记录，MRI，组织学和分子方法，线粒体记者（MT-Keima）小鼠和NADPH细胞色素B5的有条件敲除小鼠在平滑肌或神经中还原3（CYB5R3），使SGC无反应到NO•在这些细胞中。