Impact of Chemotherapy on Bladder Function in Children

项目总结/摘要 K23项目将为Nicholas G.成本，MD与受保护的时间，指导，培训，和 成为一名独立的外科医生科学家。科斯特医生是一位有资格认证的泌尿科医生， 在泌尿肿瘤学和泌尿外科肿瘤学的奖学金培训后， 小儿泌尿科他的长期愿景是尽量减少儿科癌症护理对长期患者的影响。 泌尿外科结局。具体来说，他专注于研究化疗对膀胱功能的影响。 这涉及研究儿童癌症幸存者膀胱功能障碍（BD）的流行病学， 研究化疗引起的膀胱生理学改变。这将成熟到学习 这种病理生理学背后的机制和识别化疗诱导的BD的生物标志物。技能 他将在获奖期间获得，包括：1）流行病学的教学和“动手”教育，2）先进的 膀胱生理学研究中的实验室技能，以及3）研究尿蛋白质组学和生物标志物。 该基金旨在客观地描述化疗引起的儿科疾病的患病率和程度。 BD，以及解释功能障碍的机制，以预防化疗诱导的BD。而 化疗是治疗儿童癌症的基础，已知这些疗法具有多种治疗效果。 有害的副作用有很多关于他们最常见的副作用，但一直没有 研究化疗如何影响膀胱功能。在将化疗与潜在的BD联系起来时， 在儿科肿瘤学中有两种广泛使用的药物，长春新碱（VCR）和阿霉素（DOX）， 已知引起周围神经病变（VCR）和肌毒性（DOX）。这种神经毒性和肌肉毒性可能 合理诱导BD。该补助金旨在解决这一知识差距，具体目标有三个：1） 评价VCR和/或DOX治疗儿童的BD症状; 2）确定其机制 使用小鼠模型，研究VCR和/或DOX后的基础BD; 3）评价尿蛋白质组，以及 暴露于VCR和/或DOX的儿童中BD的已知尿液生物标志物水平。第一个目标将利用 有大量儿童癌症存活者第二和第三个目标是 由成本博士的导师谁拥有在膀胱生理学创新研究的良好记录的支持。 拟议的工作具有很高的潜力，使一个显着的临床影响。这将是第一次描述 这种临床现象，并代表了必要的初步步骤，在职业生涯的长期调查， 了解和预防化疗引起的儿科BD。根据科斯特博士最初的研究， 生产力，以及强大的导师团队，建议的工作是现实和可行的奖励期内 并将提供博士成本的必要技能，以竞争未来的R 01或同等的资金。这个奖项 成本的职业生涯提供必要的支持，使他能够成为一个理想的时间 成功的独立外科医生兼科学家

PROJECT SUMMARY/ABSTRACT This K23 proposal will provide Nicholas G. Cost, MD with the protected time, mentorship, training, and experience to become an independent surgeon-scientist. Dr. Cost is a board-certified urologist with a unique practice focused on pediatric urologic oncology developed after fellowship training in both urologic oncology and pediatric urology. His long-term vision is to minimize the impact of pediatric cancer care on long-term urologic outcomes. Specifically, he is focused on studying the impact of chemotherapy on bladder function. This involves studying the epidemiology of bladder dysfunction (BD) in childhood cancer survivors and investigating alterations in bladder physiology induced by chemotherapy. This will mature into studying mechanisms behind this pathophysiology and identifying biomarkers of chemotherapy-induced BD. Skills that he will acquire during the award, include: 1) didactic and “hands on” education in epidemiology, 2) advanced laboratory skills in the study of bladder physiology, and 3) investigation into urinary proteomics and biomarkers. This grant proposes to objectively describe the prevalence and extent of chemotherapy-induced pediatric BD, as well as explain the mechanisms of dysfunction in order to prevent chemotherapy-induced BD. While chemotherapy is the foundation for treating childhood cancer, these therapies are known to have a variety of deleterious side effects. There is much known about their most common side effects, but there has been no investigation into how chemotherapy impacts bladder function. In connecting chemotherapy to potential BD, there are two widely used agents in pediatric oncology, Vincristine (VCR) and Doxorubicin (DOX), which are known to cause peripheral neuropathy (VCR) and myotoxicity (DOX). Such neurotoxicity and myotoxicity could rationally induce BD. This grant proposes to address this gap in knowledge with three specific aims: 1) To evaluate the symptoms of BD in children treated with VCR and/or DOX; 2) To determine the mechanisms underlying BD after VCR and/or DOX using a murine model; 3) To evaluate the urinary proteome, as well as levels of known urinary biomarkers of BD, in children exposed to VCR and/or DOX. The first aim will leverage a large pediatric cancer survivorship population at Dr. Cost's institution. The second and third aim will be supported by Dr. Cost's mentors who have a strong track record of innovative research in bladder physiology. The proposed work has high potential to make a significant clinical impact. It will be the first description of this clinical phenomenon and represents the necessary initial steps in a career-long investigation into understanding and preventing chemotherapy-induced pediatric BD. Based on Dr. Cost's initial work, past productivity, and strong mentorship team, the proposed work is realistic and feasible within the award period and will provide Dr. Cost the skills necessary to compete for future R01 or equivalent funding. This award comes at an ideal time in Dr. Cost's career to provide the necessary support to enable him to become a successful independent surgeon-scientist.