Role of the ubiquitin Ligase adaptor FBXL13 on Salt-sensitive hypertension

候选人：Gustavo Ares，博士，是一名研究-科学家讲师，受训于综合肾脏生理学 与亨利福特健康系统的高血压有关。在这份修订后的申请中，阿雷斯博士的目标是确定 高盐饮食是否刺激E3泛素连接酶FBXL13-NKCC2相互作用，增强NKCC2 降解，有利于氯化钠的排泄，从而防止血压升高。阿瑞斯博士的近期目标 是获得必要的研究、培训和专业技能，以过渡到独立的校外 资助的调查员。他的长期目标是建立自己的研究计划，专注于识别小说 环状利尿剂和药物干预治疗高血压的靶点。阿瑞斯博士的职业生涯 发展计划包括提高HIS：1)研究技能；2)网络和协作；3) 通过参加周刊俱乐部、研讨会、课程和 国家科学会议；4)指导技能；5)撰写手稿和赠款。阿瑞斯博士的进步将是 通过每两周一次到每月一次的会议与指导团队的每位成员进行评估。环境：阿瑞斯博士 和他的导师，已经组建了一个强大的联合导师和顾问团队来指导他完成研究 项目。主要导师：Pablo Ortiz博士，美国国立卫生研究院资助的科学家，在肾脏研究方面有很强的成功记录 生理学和高血压。二级导师：杰弗里·L·加文博士是CWRU生理学教授 克利夫兰，在调节沿肾单位的盐和水的运输方面有丰富的经验。 二级导师：加州大学欧文分校生物化学教授兼主席彼得·凯泽博士拥有广泛的 对泛素-蛋白酶体系统和E3-泛素连接酶有经验，对Skp1- 库林-FBox家族建筑群。支持性研究团队包括T.Pavlov博士和Mariela Mendez博士。 从事肾脏生理学工作；帕梅拉·哈丁博士，N-E。Rhaleb博士，Suresh Palaniyandi博士，在 心血管生理学/病理生理学。研究：高血压是一种高度流行的疾病，涉及 肾脏不能排出过多的盐分。顶端Na~+/K~+/2Cl~-对氯化钠重吸收的异常增强 联转运体(NKCC2)的Henle环(TAL)粗大上行支与盐敏感相关 人类的高血压。NKCC2抑制剂有许多副作用，因此不被使用。本项目研究 一种新的E3泛素连接酶FBXL13在正常血压调节和氯化钠重吸收中的作用 或者高盐饮食。在目标I中，我们研究了高盐对NKCC2泛素化、表面磷(Thr96-101)的影响 和Ser126)和总的NKCC2表达和活性。在AIM II中，我们将研究FBXL13-NKCC2相互作用。在……里面 目的研究FBXL13在氯化钠重吸收和血压调节中的作用。此应用程序将 增进我们的知识，这可能导致新的高血压治疗策略，并促进 新型特效环状利尿剂的开发。

Candidate: Gustavo Ares, Ph.D., is a Research-Scientist Instructor training in the integrative renal physiology related to hypertension at Henry Ford Health system. In this revised application, Dr. Ares aims to determine whether a high salt diet stimulates the E3 ubiquitin-ligase FBXL13-NKCC2 interaction, enhancing NKCC2 degradation, favoring NaCl excretion thereby preventing an increase in blood pressure. Dr. Ares' immediate goal is to acquire the research training and professional skills necessary to transition to an independent extramurally funded investigator. His long-term goal is to establish his own research program with a focus on identifying novel targets of loops diuretics and pharmacological interventions to treat hypertension. Dr. Ares' Career Development Plan consists of improving his: 1) research skills; 2) Networking and collaborations; 3) professional development through attendance of presentations at weekly journal clubs, seminars, course and national scientific meetings; 4) mentoring skills; 5) writing manuscripts and grants. Dr. Ares' progress will be assessed thru bi-weekly to monthly meetings with each member of the mentoring team. Environment: Dr. Ares and his mentor, have assembled a strong team of co-mentors and advisors to guide him through the research project. Primary mentor: Dr. Pablo Ortiz a NIH-funded scientist with strong records of successful in renal physiology and hypertension. Secondary mentor: Dr. Jeffery L. Garvin is a professor of physiology at CWRU Cleveland, with extensive experience in regulation of salt and water transport along the renal nephron. Secondary mentor: Dr. Peter Kaiser, professor and Chair of Biological Chemistry at UC Irvine, has extensive experience in the ubiquitin-proteasome system, and the E3-ubiquitin ligases with special interest in the Skp1- Cullin-FBox family complex. The supportive research team includes T. Pavlov, Ph.D. and Mariela Mendez, Ph.D. working in renal physiology; Pamela Harding Ph.D., N-E. Rhaleb, Ph.D., Suresh Palaniyandi, Ph.D. working in cardiovascular physiology/pathophysiology. Research: Hypertension is a highly prevalent condition involving the kidney's inability to excrete excess salt. Abnormally enhanced NaCl reabsorption thru the apical Na+/K+/2Cl- cotransporter (NKCC2) by the thick ascending limb of the loop of Henle (TAL) is associated with salt-sensitive hypertension in humans. NKCC2 inhibitors has many side effects, therefore they are not used. This project study the role of a novel E3 ubiquitin ligase FBXL13 on NaCl reabsorption and blood pressure regulation under normal or high salt diet. In Aim I, we study the effect of high salt on NKCC2 ubiquitination, surface phosphor (Thr96-101 and Ser126) and total NKCC2 expression and activity. In Aim II, we will study the FBXL13-NKCC2 interaction. In Aim III We study the role of FBXL13 on NaCl reabsorption and blood pressure regulation. This application will advance our knowledge which may lead to new strategies for the treatment of hypertension and promote the development of novel and specific loop diuretics.