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Developing a Next Generation Mouse Model of Urogenital Schistosomiasis Through Ultrasound-Guided Percutaneous Bladder Wall Injection of Schistosoma haematobium Eggs

通过超声引导经皮膀胱壁注射埃及血吸虫卵开发下一代泌尿生殖血吸虫病小鼠模型

基本信息

批准号：
10171777
负责人：
Michael Harrison Hsieh
金额：
$ 17.85万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-11-30
项目状态：
已结题

项目摘要

The bladder is frequently involved in urogenital schistosomiasis, primarily infection by Schistosoma haematobium worms. Urogenital schistosomiasis is the most common form of schistosomiasis worldwide and is estimated to affect at least 112 million people. Another 436 million individuals are at risk of infection. We and others have shown that deposition of S. haematobium eggs in the bladder induces type 2 inflammation-mediated, bladder-specific sequelae such as hematuria, urinary frequency, urothelial hyperplasia, and bladder carcinogenesis. Treatment with praziquantel can reverse early, mild bladder pathology in approximately 75% of patients, but fails to cure advanced pathology. There is a critical need to better understand the earliest host responses to egg deposition in order to identify new approaches to prevent progression to advanced bladder pathology. However, it is difficult to study early schistosomal bladder pathology in humans, since the onset of egg deposition in the bladder is uncertain in most affected individuals, and it is unethical to perform medically unnecessary bladder biopsies in these individuals to obtain tissue. Natural infection of mice with S. haematobium cercariae, the infective larval stage for humans, does not result in bladder involvement. Thus, natural infection of mice is a poor model for schistosomal bladder pathogenesis. Nevertheless, failing to advance our understanding of schistosomal bladder pathology will perpetuate the 150,000 annual deaths caused by obstructive renal failure secondary to schistosomal bladder fibrosis. To address this knowledge gap, we developed the first tractable mouse model of urogenital schistosomiasis. In this model, mice undergo laparotomy, the bladder is exteriorized, and then S. haematobium eggs are injected into the bladder wall. S. haematobium egg injection triggers hematuria, urinary frequency, urothelial hyperplasia, and granulomatous fibrosis, akin to human urogenital schistosomiasis. However, this model is limited by its dependence on laparotomy, which results in non- specific local and systemic inflammation. Thus, the current mouse model of urogenital schistosomiasis may not optimally reflect human disease due to confounding, non-specific immune effects of laparotomy. Other workers have refined the bladder wall injection technique by using ultrasound to guide percutaneous injection of tumor cells into the bladder wall, which avoids a laparotomy. The goal of this application is to develop a next generation model of schistosomal bladder pathogenesis through use of ultrasound-guided, percutaneous injection of the mouse bladder wall with S. haematobium eggs. Once our project is completed, we will have more precise knowledge regarding early bladder changes induced by S. haematobium eggs, unhindered by any confounding immune effects of laparotomy. Completion of this project will improve animal welfare and have a positive impact on urogenital schistosomiasis research by helping to find novel therapeutic targets to prevent early schistosomal bladder pathology from advancing to irreversible disease.

膀胱是经常涉及泌尿生殖道血吸虫病，主要是血吸虫感染埃及血蠕虫泌尿生殖道血吸虫病是世界范围内最常见的血吸虫病估计至少有一亿一千二百万人受到影响。另有4.36亿人面临感染风险。我们和其他人已经表明，沉积的S。膀胱中的血吸虫卵诱导2型炎症介导的膀胱特异性后遗症，如血尿、尿频、尿路上皮疾病、增生和膀胱癌发生。吡喹酮治疗可逆转早期轻度膀胱炎在大约75%的患者中，这种方法治疗病理学，但未能治愈晚期病理学。迫切需要更好地了解最早的宿主对卵沉积的反应，以确定新的方法，防止进展为晚期膀胱病理。然而，研究早期染色体异常是困难的，人类膀胱病理学，因为在大多数受影响的膀胱中卵沉积的开始是不确定的，个体，并且在这些个体中进行医学上不必要的膀胱活检是不道德的，获取组织。小鼠自然感染S.血吸虫尾蚴，感染性幼虫阶段，人类，不会导致膀胱受累。因此，小鼠的自然感染是一个很差的模型，膀胱炎的发病机制。尽管如此，未能推进我们的理解，膀胱病理学将使每年150，000例因继发性梗阻性肾衰竭而死亡的病例永久化，膀胱纤维化为了弥补这一知识缺口，我们开发了第一只易驾驭的鼠标，泌尿生殖道血吸虫病模型。在该模型中，小鼠经历剖腹手术，膀胱外置，然后是S。将血蜱卵注入膀胱壁。S.血吸虫卵注射触发器血尿、尿频、尿路上皮增生和肉芽肿性纤维化，类似于人类泌尿生殖系统血吸虫病然而，该模型受到其对剖腹手术的依赖的限制，这导致非- 特异性局部和全身炎症。因此，目前的泌尿生殖道血吸虫病小鼠模型可能由于剖腹手术的混杂、非特异性免疫作用，不能最佳地反映人类疾病。其他工作人员通过使用超声引导经皮穿刺，将肿瘤细胞注射到膀胱壁中，这避免了剖腹手术。此应用程序的目标是通过使用超声引导，经皮注射小鼠膀胱壁S.血吸虫卵一旦我们的项目完成后，我们将有更精确的知识，早期膀胱的变化引起的S。不受剖腹手术的任何混杂免疫效应的阻碍。完成本该项目将改善动物福利，并对泌尿生殖道血吸虫病研究产生积极影响，有助于发现新的治疗靶点，以防止早期膀胱癌病理进展到不可逆的疾病