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

候选人：古斯塔沃战神，博士，是一名接受综合肾脏生理学培训的研究科学家导师 亨利福特医疗系统的高血压相关的病人在这份修订后的申请中，战神博士的目标是确定 高盐饮食是否刺激E3泛素连接酶FBXL 13-NKCC 2相互作用，增强NKCC 2 降解，有利于NaCl排泄，从而防止血压升高。战神博士的近期目标 是获得必要的研究培训和专业技能，过渡到一个独立的校外 资助的调查员。他的长期目标是建立自己的研究计划，重点是确定新的 袢利尿剂和药物干预治疗高血压的目标。战神博士的职业生涯 发展计划包括提高他的：1）研究技能; 2）网络和合作; 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。战神博士的进展 通过每两周一次或每月一次与指导团队的每个成员举行会议进行评估。环境：战神博士 和他的导师，已经组建了一个强大的团队的共同导师和顾问，以指导他通过研究 项目主要导师：巴勃罗奥尔蒂斯博士，NIH资助的科学家，在肾脏疾病治疗方面有着成功的记录。 生理学和高血压。第二导师：Jeffery L博士。加文是CWRU的生理学教授 Cleveland，在调节盐和水沿肾单位沿着运输方面具有丰富的经验。 二级导师：Peter Kaiser博士，加州大学欧文分校生物化学教授兼主席， 在泛素-蛋白酶体系统方面的经验，以及E3-泛素连接酶，特别关注Skp 1- Cullin-FBox家族综合体。支持性研究团队包括T.巴甫洛夫博士Mariela Mendez博士 从事肾脏生理学研究;帕梅拉·哈丁博士，东北Rhaleb博士，Suresh Palaniyandi博士工作 心血管生理学/病理生理学。研究：高血压是一种非常普遍的疾病， 肾脏无法排出多余的盐分通过顶端Na+/K+/2Cl-的NaCl重吸收异常增强 Henle袢（TAL）粗升支的协同转运蛋白（NKCC 2）与盐敏感性相关。 人类的高血压NKCC 2抑制剂有许多副作用，因此不使用。本项目研究 E3泛素连接酶FBXL 13在正常血压下对NaCl重吸收和血压调节中作用 或高盐饮食。在目的I中，我们研究了高盐对NKCC 2泛素化、表面磷（Thr 96 -101）的影响， 和Ser 126）和总NKCC 2表达和活性。在目的II中，我们将研究FBXL 13-NKCC 2相互作用。在 目的III研究FBXL 13在NaCl重吸收和血压调节中的作用。此应用程序将 推进我们的知识，这可能导致新的战略，为治疗高血压和促进 开发新的和特定的袢利尿剂。

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.