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

• 批准号: 10041747
• 负责人: Michael Harrison Hsieh
• 金额: $ 30.16万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041747
• 关键词: Address; Affect; Animal Model; Animal Welfare; Animals; Biopsy; Bladder; Bypass; Cause of Death; Cessation of life; Dependence; Deposition; Detection; Disease; Fibrosis; Genitourinary system; Goals; Granulomatous; Hematuria; Human; Immune; Immune response; Increased frequency of micturition; Individual; Infection; Inflammation; Injections; Kidney Failure; Knowledge; Laparotomy; Malignant neoplasm of urinary bladder; Mediating; Medical; Methods; Modeling; Mus; Outcome; Pathogenesis; Pathology; Patients; Postoperative Pain; Praziquantel; Primary Infection; Research; Rodent; Schistosoma haematobium; Schistosomiasis; Secondary to; Techniques; Tissues; Ultrasonography; Urothelial Hyperplasia; Urothelium; World Health Organization; Xenograft procedure; advanced disease; carcinogenesis; carcinogenicity; egg; human disease; improved; infection risk; innovation; minimally invasive; mouse model; neoplastic cell; new therapeutic target; next generation; novel strategies; pathogen; prevent

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.

膀胱常累及泌尿生殖系统血吸虫病，主要由血吸虫感染。 血瘤杆菌蠕虫。泌尿生殖系统血吸虫病是全世界最常见的血吸虫病形式。 据估计，至少有1.12亿人受到影响。另有4.36亿人面临感染风险。 我们和其他人已经证明，血结核杆菌卵在膀胱中的沉积会导致2型。 炎症介导的膀胱特异性后遗症，如血尿、尿频、尿路上皮 增生和膀胱癌的发生。吡喹酮治疗可逆转早期轻度膀胱 约75%的患者有病理改变，但未能治愈晚期病理改变。迫切需要 更好地了解寄主对卵子沉积的最早反应，以便确定新的方法 防止进展为晚期膀胱病理。然而，对早期血吸虫的研究是困难的 在人类膀胱病理中，由于卵子沉积在膀胱的起始期是不确定的，因此在大多数情况下受到影响 在这些人身上进行医学上不必要的膀胱活检是不道德的 获取组织。小鼠自然感染尾蚴嗜血杆菌，感染幼虫阶段 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 血吸虫膀胱发病机制。然而，未能提高我们对血吸虫的认识 膀胱病理将使每年因梗阻性肾功能衰竭导致的15万人死亡永久化 血吸虫性膀胱纤维化。为了解决这一知识鸿沟，我们开发了第一只易驯服的鼠标 泌尿生殖系统血吸虫病模型。在这个模型中，小鼠接受剖腹手术，膀胱被外置， 然后将血瘤链球菌的卵子注射到膀胱壁。美国血吸虫卵子注射引发 类似人类泌尿生殖系统的血尿、尿频、尿路上皮增生和肉芽肿性纤维化 血吸虫病。然而，这种模式受到其对剖腹手术的依赖的限制，这导致了非 特殊的局部和全身炎症。因此，目前的尿路血吸虫病小鼠模型可能 不能最好地反映人类疾病由于混淆、非特异性免疫的影响而剖腹手术。其他 工作人员通过使用超声波引导经皮注射改进了膀胱壁注射技术 将肿瘤细胞注入膀胱壁，避免了剖腹手术。此应用程序的目标是 利用超声引导建立下一代血吸虫膀胱致病模型， 小鼠膀胱壁经皮注射血瘤链球菌虫卵。一旦我们的项目 完成后，我们将更准确地了解S。 血吸虫卵，不受剖腹手术的任何混淆免疫效果的阻碍。完成这项工作 该项目将改善动物福利，并对泌尿生殖系统血吸虫病研究产生积极影响 帮助寻找新的治疗靶点，以防止早期血吸虫病膀胱病理进展到 不可逆转的疾病。