Role of Wnt signaling in uremia-induced entothelial dysfunction

说明： 慢性肾功能衰竭(CRF)和终末期肾病(ESRD)是世界性的公共卫生问题和巨大的经济负担。仅在美国，今天就有800万至1000万人患有慢性肾功能衰竭。心血管疾病(CVD)是慢性肾功能衰竭最常见的致病原因，占CRF患者死亡的50%以上。内皮功能障碍是心血管疾病的重要因素，在慢性肾功能衰竭患者中普遍存在。然而，这些患者中涉及内皮功能障碍的信号通路仍不清楚。 这项拟议的研究将侧重于细胞内信号在CRF患者内皮功能障碍中的作用。这些实验将需要探索Wnt信号通路在内皮功能障碍的分子发病机制中的作用。这可能是一种新的治疗策略，并可能对CRF患者产生明显的好处。具体目的包括检测尿毒症血清(来自终末期肾病患者的血清)对培养内皮细胞功能的调节；在尿毒症动物模型中确定上调Wnt信号是否保护内皮细胞免受尿毒症毒性。这项工作将是首次对信号通路在尿毒症诱导的内皮功能障碍中的作用进行详细的功能分析。 申请者是一名医学讲师，正在攻读赫伯特·T·科恩博士实验室波士顿大学医学院分子医学研究生项目的博士学位。他在基础细胞和分子生物学方面有6年的经验，在内皮生物学方面有6个月的经验。他坚定地致力于肾脏病学部以基础科学为中心的职业生涯。Elazer Edelman博士是Pi的导师，是血管生物学领域公认的领导者，也是哈佛医学院医学系的教授。这项工作将在埃德尔曼博士实验室蓬勃发展的研究环境中进行，该实验室位于麻省理工学院哈佛-麻省理工学院健康科学与技术部，拥有90名研究科学家和附属教师。赞助商和合作者在这一蓬勃发展的环境中的综合专业知识将为申请者提供一个实现项目目标并成为成功的独立调查员的绝佳机会。 公共卫生相关性：这些研究可能有助于描绘Wnt信号在尿毒症中的新作用，并设计进一步的研究，以探索Wnt信号在CRF患者CVD中的诊断/预后和治疗益处。

DESCRIPTION: Chronic renal failure (CRF) and end stage renal disease (ESRD) are worldwide public health problems and an enormous economic burden. In the United States alone, today 8-10 million individuals suffer from CRF. Cardiovascular disease (CVD) is the most common cause of chronic morbidity and accounts for more than 50% of the deaths in CRF patients. Endothelial dysfunction contributes significantly to CVD and is universal in CRF patients. However, signaling pathways involved in endothelial dysfunction in these patients remain unknown. The proposed research will focus on the role of intracellular signaling in endothelial dysfunction in patients with CRF. The experiments will entail exploration of Wnt signaling pathway in molecular pathogenesis of endothelial dysfunction. Potentially this can be a novel therapeutic strategy and may have porfound benefits in CRF patients. The specific aims include examining the functions of cultured endothelial cells exposed to uremic serum (serum from patients with ESRD) with modulating Wnt signaling; determining if upregulation of Wnt signaling protects endothelial cells from uremic toxicity in a uremic animal model. This work will be the first detailed functional analysis of the role of signaling pathway in uremia-induced endothelial dysfunction. The applicant is an Instructor in Medicine and is pursing a Ph.D. in the Graduate Program of Molecular Medicine at Boston University School of Medicine in Dr. Herbert T. Cohen's laboratory. He has 6 years experience in basic cellular and molecular biology and 6 months experience in endothelial biology. He is deeply committed to a career centered on basic science in an academic division of Nephrology. Dr. Elazer Edelman, the mentor for PI, is a recognized leader in the field of vascular biology and a Professor in the Department of Medicine at Harvard Medical School. The work will be performed in the thriving research environment of Dr. Edelman's laboratory, home to 90 research scientists and affiliated faculty, located at MIT in the Harvard-MIT Division of Health Sciences and Technology. The combined expertise of the sponsor and collaborators within this thriving environment will provide an outstanding opportunity for the applicant to achieve the goals of the project and to become a successful independent investigator. PUBLIC HEALTH RELEVANCE: These studies may help to delineate a novel role for Wnt signaling in uremia and design further studies to explore both the diagnostic/prognostic and therapeutic benefits of Wnt signaling in CVD in CRF patients.