Role of Wnt signaling in uremia-induced entothelial dysfunction

慢性肾功能衰竭（CRF）和终末期肾病（ESRD）是全球性的公共卫生问题， 巨大的经济负担。仅在美国，今天就有800万至1000万人患有CRF。 心血管疾病（CVD）是慢性疾病的最常见原因， 50%的CRF患者死亡。血管内皮功能障碍是心血管疾病的重要原因，具有普遍性 在CRF患者中。然而，在这些患者中，参与内皮功能障碍的信号通路仍然存在， 未知 拟议的研究将集中在细胞内信号转导在内皮功能障碍中的作用， CRF患者。这些实验将需要探索Wnt信号通路在分子生物学中的作用。 内皮功能障碍的发病机制。这可能是一种新的治疗策略， 在CRF患者中证实了益处。具体目的包括检测培养的内皮细胞的功能， 细胞暴露于尿毒症血清（来自ESRD患者的血清），调节Wnt信号传导;确定 在尿毒症动物模型中，Wnt信号的上调是否保护内皮细胞免受尿毒症毒性。这 这项工作将是第一个详细的功能分析的作用，信号通路在尿毒症诱导的 内皮功能障碍 申请人是一名医学讲师，正在攻读博士学位。分子生物学研究生课程 波士顿大学医学院的医学博士赫伯特T。科恩的实验室他有6年 基础细胞和分子生物学经验和6个月内皮生物学经验。他是 致力于肾脏病学学术部门基础科学的职业生涯。Elazer医生 Edelman是PI的导师，是血管生物学领域公认的领导者， 哈佛医学院医学系。这项工作将在蓬勃发展的研究中进行 Edelman博士实验室的环境，拥有90名研究科学家和附属教师，位于麻省理工学院 哈佛-麻省理工学院健康科学与技术部。申办者的综合专业知识和 在这个蓬勃发展的环境中的合作者将为申请人提供一个出色的机会， 实现项目目标，成为一名成功的独立调查员。

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.