The TWIK 2 POTASSIUM CHANNELS ROLE IN THE DEVELOPMENT OF PULMONARY HYPERTENSION

描述(由申请人提供)： 项目摘要/摘要本职业发展建议旨在为首席研究员Lavannya M.Pandit博士提供必要的知识、技能和经验，以便她过渡到肺动脉高压领域的独立翻译研究员。潘伟迪医生是一位训练有素的肺部专家，在过去的八年里，他一直在照顾因晚期肺部疾病而患有肺动脉高压的退伍军人。她为这个项目带来了强大的研究背景，包括获取和处理人类肺组织的独特技能。潘伟迪博士概述了一项为期四年的计划，旨在研究一种新的钾通道Twik-2调节肺动脉张力的基本机制，特别是它如何参与肺血管收缩，这是肺动脉高压的一个决定性特征。这项工作将在医学副教授、迈克尔·E·德贝基退伍军人医学中心(MEDVAMC)肺/重症护理/睡眠医学科科长罗兰多·伦伯特博士的指导下进行。这项建议的共同导师是DeBakey VAMC的附属学术机构贝勒医学院的麻醉学教授兼脑血管研究主任罗伯特·M·布莱恩博士。这两位导师都曾作为血管生理学家相互合作，并拥有指导年轻研究人员在学术医学领域取得成功的资金和记录。潘伟迪博士还得到了MEDVAMC、贝勒医学院和卫理公会医院杰出合作者团队的支持。此外，潘伟迪博士还将在贝勒医学院临床科学家培训计划的框架内，通过心血管生理学的教学课程获得培训。潘伟迪博士过去的学术经验强调了她对学术医学的承诺，以及她在肺动脉高压方面进行转化性研究的愿望。在完成了NIH的研究培训拨款后，自2011年以来，她的研究逐渐专注于钾通道在调节肺血管张力中的作用，以努力将她的研究与她的临床专业知识相结合 发生在肺动脉高压中。她现在需要在这段科学研究的指导期内接受人类和小鼠疾病模型的肺生理学培训。这项提案中的研究将集中在Twik-2在肺动脉高压发展中的作用。科学方法将涉及利用twik-2基因已被基因敲除的小鼠的肺血管，以及通过肺移植获得的新鲜移植的来自患有和不患有肺动脉高压的患者的自然人类肺血管。该项目的具体目标是描绘Twik-2如何影响肺平滑肌细胞的电特性、细胞内钙水平和肺血管的收缩特性。通过这笔赠款获得的科学培训将导致出版出版物和经验，使候选人能够在未来四年内获得独立资金，并使自己成为一名肺动脉高压的翻译研究员。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT This career development proposal is designed to provide the Principal Investigator, Dr. Lavannya M. Pandit, with the necessary knowledge, skills, and experience required for her transition to an independent translational researcher in the field of pulmonary hypertension. Dr. Pandit is a well-trained pulmonary specialist who has cared for veterans with pulmonary hypertension due to advanced lung disease for the last eight years. She brings a strong research background to this project including unique skills in obtaining and handling human lung tissue. Dr. Pandit outlines a four-year plan to investigate the basic mechanism by which a novel potassium channel, TWIK-2, regulates pulmonary arterial tone, and specifically how it participates in pulmonary vasoconstriction, a defining characteristic of pulmonary hypertension. This work will be performed under the mentorship of Dr. Rolando Rumbaut, Associate Professor of Medicine, and Section Chief of the Pulmonary/Critical Care/Sleep Medicine section at the Michael E. DeBakey VA Medical Center (MEDVAMC). The co-mentor on this proposal is Dr. Robert M. Bryan, Professor of Anesthesiology and Director of Cerebrovascular Research at Baylor College of Medicine, the affiliated academic institution of the DeBakey VAMC. Both mentors have collaborated with each other as vascular physiologists and have the funding and track record of mentoring young investigators for successful careers in academic medicine. Dr. Pandit also has the support of a team of exceptional collaborators at MEDVAMC, Baylor College of Medicine, and the Methodist Hospital. In addition, Dr. Pandit will acquire training through didactic coursework in cardiovascular physiology within the structure of the Baylor College of Medicine Clinical Scientist Training Program. Dr. Pandit's past academic experiences underscore her commitment to academic medicine and her desire to pursue translational research in pulmonary hypertension. Having completed an NIH research training grant, since 2011, her research has evolved to focus on the role of potassium channels in the regulation of pulmonary vascular tone in an effort to meld her research with her clinical expertise in pulmonary hypertension. She now requires training in pulmonary physiology in both human and murine models of disease during this mentored period of scientific investigation. The research in this proposal will focus on the role of TWIK-2 in the development of pulmonary hypertension. The scientific approach will involve the utilization of pulmonary vessels of mice in which the TWIK-2 gene has been genetically knocked out as well as freshly explanted native human pulmonary vessels from patients with and without pulmonary hypertension, obtained at lung transplantation. Specific Aims of the project are to delineate how TWIK-2 affects the electrical properties of pulmonary smooth muscle cells, intracellular calcium levels, and the contractile properties of pulmonary vessels. The scientific training obtained through this grant will lead to publications and experience that will enable the candidate to secure independent funding within the next four years and establish herself an a translational investigator in pulmonary hypertension.