Impact of Chemotherapy on Bladder Function in Children

化疗对儿童膀胱功能的影响

• 批准号: 10397688
• 负责人: Nicholas G Cost
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397688
• 关键词: Address; Adenosine Triphosphate; Adult; Affect; Area; Award; Biological Markers; Bladder; Bladder Dysfunction; Brain-Derived Neurotrophic Factor; Cancer Survivor; Cancer Survivorship; Cardiac; Caregivers; Caring; Chemotherapy-Oncologic Procedure; Child; Childhood; Clinical; Clinical Data; Communities; Complex; Data; Disease; Doxorubicin; Education; Ensure; Epidemiology; Exhibits; Exposure to; Failure; Fellowship; Foundations; Functional disorder; Funding; Future; Gender; Goals; Grant; Health; Heart failure; Institution; Investigation; Kidney; Knowledge; Laboratories; Late Effects; Life; Malignant Childhood Neoplasm; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Mus; Muscle; Nerve Growth Factors; Neurogenic Bladder; Oncologist; Outcome; Patients; Pediatric Oncology; Peripheral Nervous System Diseases; Physiological; Physiology; Population; Prevalence; Price; Productivity; Proteome; Proteomics; Publishing; Quality of life; Research; Research Personnel; Risk; Scientist; Second Primary Cancers; Societies; Surgeon; Surveys; Survivors; Symptoms; System; Time; Training; United States; Urologic Oncology; Urologist; Urology; Vincristine; Vision; Work; base; cancer care; cancer therapy; career; chemotherapy; childhood cancer survivor; cost; experience; follow-up; gonad function; health related quality of life; individual patient; innovation; mouse model; neurotoxicity; prevent; psychosocial; relating to nervous system; side effect; skills; success; survivorship; trend; urinary; urologic

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.

项目摘要/摘要 这项K23计划将为Nicholas G.Cost医学博士提供受保护的时间、指导、培训和 成为一名独立的外科医生兼科学家的经验。科斯博士是一名经过委员会认证的泌尿科医生，拥有独特的 在两个泌尿外科肿瘤学的团契培训后，专注于儿科泌尿外科肿瘤学 和儿科泌尿科。他的长期愿景是将儿科癌症护理对长期 泌尿科的结果。具体地说，他专注于研究化疗对膀胱功能的影响。 这涉及到研究儿童癌症幸存者的膀胱功能障碍(BD)的流行病学和 研究化疗引起的膀胱生理改变。这将成熟为学习 化疗所致BD的病理生理机制和生物标记物的识别。具备以下技能的 他将在获奖期间获得包括：1)流行病学的教学和实践教育，2)高级 膀胱生理学研究的实验室技能，以及3)尿蛋白组学和生物标记物的研究。 这项拨款建议客观地描述化疗引起的儿童癌症的患病率和程度。 并解释其功能障碍的机制，以预防化疗所致的BD。而当 化疗是治疗儿童癌症的基础，众所周知，这些治疗方法有多种 有害的副作用。关于它们最常见的副作用，人们知道得很多，但还没有 研究化疗对膀胱功能的影响。在将化疗与潜在的BD联系起来时， 长春新碱(VCR)和多柔比星(DOX)是儿科肿瘤学中广泛使用的两种药物，它们是 已知会导致周围神经病(VCR)和肌肉毒性(DOX)。这种神经毒性和肌肉毒性可能 合理诱导BD。这笔赠款建议用三个具体目标来解决这一知识差距：1) 评估接受VCR和/或DOX治疗的儿童BD的症状；2)确定其机制 使用小鼠模型研究VCR和/或DOX后潜在的BD；3)评估尿蛋白质组，以及 接触VCR和/或DOX的儿童中已知的BD尿生物标志物水平。第一个目标将利用 成本医生机构的大量儿科癌症存活者。第二和第三个目标将是 在成本博士的导师的支持下，这些导师在膀胱生理学的创新研究方面有着良好的记录。 这项拟议的工作有很高的潜力产生重大的临床影响。这将是第一次描述 这一临床现象代表了一项职业生涯中对 儿童化疗所致BD的认识和预防。基于Cost博士最初的工作，过去 生产力，以及强大的指导团队，建议的工作在获奖期内是现实和可行的 并将为Dr.Cost提供竞争未来R01或同等资金所需的技能。本奖项 在成本博士职业生涯的理想时刻提供必要的支持，使他能够成为一名 成功的独立外科医生兼科学家。