The effect of congenital renal obstruction on the urinary proteome in infants

描述(由申请人提供)： 随着超声产前筛查的使用越来越多，越来越多的胎儿被诊断为可能患有先天性肾梗阻(占美国所有妊娠的2%-5%)。到目前为止，儿童肾功能衰竭最常见的原因是尿路梗阻引起的肾脏损害。对于患有这种疾病的儿童的发现、预后和适当的治疗，存在许多争议。 我们假设先天性肾梗阻导致特定蛋白释放到尿液中，这些蛋白反映了蛋白分泌的变化，并从肾小管细胞和其他来源脱落。我们预测，这些变化将随梗阻的发病、持续时间和严重程度而变化。在我们之前的工作中，我们已经证明了我们能够使用最先进的质谱学和蛋白质组学方法在出生后成熟的动物模型中鉴定尿蛋白组学中的蛋白质。有了这次经验，我的目标是确定新的梗阻性肾损害标志物，可能成为潜在的诊断或预后临床工具。我们的方法是使用新生儿肾梗阻的动物模型，并跟踪损伤开始后一段时间内的尿液成分。我们将使用先进的定性和定量蛋白质组学方法研究梗阻期间的尿蛋白质组，以便优先选择和确定候选的临床标记物。候选标记物的鉴别能力及其临床翻译的潜力将通过在有和没有严重肾梗阻的精选人类婴儿队列中使用定向定量蛋白质组学来确定。 总体而言，我的长期职业目标是成为一名独立的儿科泌尿外科临床医生兼科学家，坚定地致力于转化性研究，专注于肾脏损伤的生物标记物发现。我的近期目标是在质谱学、蛋白质组学和生物标记物验证方面获得强大的背景和研究经验。在我职业生涯的早期，我计划通过演讲、Michael Freeman博士和其他人的强大指导、科学合作、实践经验和专注于蛋白质组学、临床试验、生物标记物、流行病学和生物信息学的教学课程，来加强我作为临床研究员的基础。我的研究将在波士顿儿童医院、泌尿系疾病研究中心和波士顿儿童医院蛋白质组学中心进行。总而言之，该项目将为作为一名独立研究人员的成功职业生涯提供必要的基础，并将导致识别可用于指导受先天性肾梗阻影响的儿童的临床决定的新生物标记物。

DESCRIPTION (provided by applicant): With the increased use of prenatal screening by ultrasound, more fetuses are being diagnosed as potentially having congenital renal obstruction (2-5% of all pregnancies in the US). To date, the most common cause of renal failure in children is from renal damaged caused by urinary obstruction. Many controversies exist regarding detection, prognosis, and proper management of children with this condition. We hypothesize that congenital renal obstruction results in the release of specific proteins into the urine that reflect changes in protein secretion and shedding from renal tubular cells and other sources. We predict that these changes will vary with onset, duration and severity of the obstruction. In our previous work, we have demonstrated our ability to use state-of-the-art mass spectrometric and proteomic approaches to identify proteins in the urinary proteome in an animal model of postnatal maturation. With this experience, my objective is to identify new markers of obstructive renal damage that could be potential diagnostic or prognostic clinical tools. Our approach will be to use an animal model of neonatal renal obstruction and follow urine composition over time after initiation of the injury. We will study the urinary proteome during obstruction using advanced qualitative and quantitative proteomic methodologies in order to prioritize and identify candidate clinical markers. The discriminatory power of the candidate markers, and their potential for clinical translation, will be determined using directed quantitative proteomics in select human infant cohorts with and without severe renal obstruction. Overall, my long-term career objective is to become an independent pediatric urologic clinician-scientist with a strong commitment to translational research that focuses on biomarker discovery for renal injury. My immediate goals are to acquire a strong background and research experience in mass spectrometry, proteomics, and biomarker validation. During the early portion of my career, I plan to add to my foundation as a clinician investigator through lectures, strong mentorship by Dr. Michael Freeman and others, scientific collaborations, hands-on experience, and didactic coursework that focuses on proteomics, clinical trials, biomarkers, epidemiology, and bioinformatics. My research will be conducted at Children's Hospital Boston in the Urological Diseases Research Center and in the Children's Hospital Boston Proteomics Center. In summary, this project will provide the necessary foundation for a successful career as an independent investigator and will lead to the identification of novel biomarkers that may be used to inform clinical decisions in children affected with congenital renal obstruction.