Regulation of pulmonary vascular cell redox state by L-2-hydroxyglutarate

L-2-羟基戊二酸对肺血管细胞氧化还原状态的调节

• 批准号: 9900849
• 负责人: William Michael Oldham
• 金额: $ 17.24万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900849
• 关键词: Address; Advisory Committees; Affect; Animal Model; Apoptosis; Area; Award; Biochemical; Biochemical Pathway; Biochemistry; Biological Assay; Blood Pressure; Blood Vessels; Cell Culture Techniques; Cell Proliferation; Cells; Chemistry; Clinical; Communities; Critical Care; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Energy Metabolism; Environment; Enzymes; Exposure to; Funding; Future; Generations; Glucose; Glutathione Reductase; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Goals; Grant; Growth; Heart; Heart failure; Homeostasis; Hospitals; Human; Hypoxia; In Vitro; Internal Medicine; International; Investigation; Investigational Therapies; Isocitrate Dehydrogenase; K-Series Research Career Programs; Laboratories; Link; Lung; Lung diseases; Malignant Neoplasms; Maps; Measurement; Measures; Medical; Medicine; Mentors; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Monocrotaline; Morbidity - disease rate; Mus; Mutation; NADH; NADP; NADPH Oxidase; Outcome; Oxidation-Reduction; Oxides; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Pentosephosphate Pathway; Pharmacology; Phenotype; Physicians; Physiology; Plasma; Play; Principal Investigator; Production; Pulmonary Hypertension; Pulmonary artery structure; Pulmonology; Rattus; Reactive Oxygen Species; Reduced Glutathione; Regulation; Research; Resistance; Right Ventricular Dysfunction; Role; Scientist; Signal Transduction; Smooth Muscle Myocytes; Stress; Superoxides; Systolic Pressure; Techniques; Testing; Time; Training; Training Programs; United States National Institutes of Health; Universities; Vascular Diseases; Vascular remodeling; Venous; Ventricular; Woman; Work; biochemical model; cancer cell; career; career development; cell growth; design; enantiomer; experience; experimental study; genetic manipulation; in vivo; innovation; instructor; kinetic model; medical schools; member; metabolomics; mitochondrial membrane; mortality; novel; oxidation; pressure; programs; public health relevance; pulmonary arterial hypertension; response; skills; stress reduction; stressor; targeted treatment; therapeutic target; therapy development; tool; transcription factor; translational impact

 DESCRIPTION (provided by applicant): The NIH Mentored Clinical Scientist Research Career Development Award (K08) proposal describes a five- year training program for career development in academic pulmonary medicine. The principal investigator, William Oldham, M.D., Ph.D., is an Associate Physician and Instructor of Medicine in the Division of Pulmonary and Critical Care Medicine at the Brigham and Women's Hospital (BWH) and Harvard Medical School. He has a background in chemistry and biochemistry and completed doctoral research in pharmacology while a member of the NIH Medical Scientist Training Program at Vanderbilt University. He completed clinical training in Internal Medicine, Pulmonary Disease, and Critical Care Medicine in 2012. His goal is to develop a successful career as an independently funded physician-scientist investigating redox metabolism in pulmonary vascular disease. With the support and protected time provided by the K08 award, Dr. Oldham will develop expertise in the fields of energy metabolism, redox biochemistry, mitochondrial physiology, and dynamic modeling from formal coursework, independent study, and practical experience with relevant experimental techniques. Dr. Joseph Loscalzo, an internationally recognized expert in these areas with over 30 years of mentoring experience, will mentor Dr. Oldham with the support of an advisory committee composed of outstanding scientists in metabolism and pulmonary disease. As the award period progresses, Dr. Oldham will develop the skills necessary for a successful R01 grant submission. Dr. Oldham will work in the Division of Pulmonary and Critical Care Medicine in the Department of Medicine at BWH, an outstanding scientific and mentoring environment located within the heart of the Harvard Medical School community. Pulmonary arterial hypertension affects 15-50 people per million and elevated pulmonary artery pressures con- tribute to increased morbidity and mortality of millions more affected by lung disease, heart failure, and other conditions. Metabolic abnormalities in PAH offer a rich potential for the development of much-needed disease modifying therapies for this condition. Dr. Oldham's long-term goal is to define the metabolic derangements underlying PAH and to develop therapies targeting the resulting metabolic vulnerabilities. The overall objective of this application is to define the role of L2HG in the pathogenesis of PAH as the first step toward his long- term goal. The central hypothesis is that L2HG production supports pulmonary vascular remodeling in PAH by increasing pro-proliferative reactive oxygen species generation in pulmonary vascular cells. The rationale for this proposal is that, once the links between L2HG metabolism and PAH pathogenesis are defined, these bio- chemical pathways can be targeted pharmacologically, resulting in novel and disease-modifying therapies for PAH. The central hypothesis will be tested by pursuing the following specific aims: (1) Determine the biochemical link between L2HG metabolism, glycolysis, and cellular redox state using biochemical and kinetic modeling approaches; (2) Determine the impact of L2HG metabolism on pulmonary vascular cell phenotype using genetic manipulations of L2HG levels and readouts of cell proliferation, apoptosis, and reactive oxygen species production; and (3) Determine the role of L2HG metabolism in the development of PAH using genetically modified mice. The contribution of this work is expected to be a mechanistic understanding of how L2HG metabolism regulates cellular redox homeostasis in support of pulmonary vascular remodeling in PAH. This contribution will be significant because it will define a critical role for L2HG in normal and diseased metabolism that will enhance our understanding of the cellular response to hypoxia and other stressors. The proposed research is innovative because it represents a new and substantive departure from the status quo by defining an important role for L2HG metabolism in cellular redox homeostasis. This research will open new horizons in the study of intracellular redox signaling. Moreover, this pathway has not been previously associated with PAH and represents a new area for mechanistic investigations of disease pathogenesis. Since L2HG is not an intermediate in any known metabolic pathway, its metabolism may offer safe and tractable experimental and therapeutic tar- gets for manipulating cellular redox state, which would provide a valuable tool for future investigations of this deadly disease.

 描述（由适用提供）：NIH指导的临床科学家研究职业发展奖（K08）提案描述了一项为期五年的学术肺医学培训计划。首席研究员威廉·奥尔德姆（William Oldham），医学博士，博士学位，是杨百翰及妇女医院（BWH）和哈佛医学院的肺和重症监护医学司的副医师和教练。他具有化学和生物化学的背景，并完成了药理学博士研究，而范德比尔特大学NIH医学科学家培训计划的成员。他于2012年完成了内科，肺部疾病和重症监护医学的临床培训。他的目标是作为一个独立资助的身体科学家，研究肺血管疾病中的氧化还原代谢的成功事业。借助K08奖提供的支持和受保护的时间，Oldham博士将在能源代谢，氧化还原生物化学，线粒体生理学以及与相关实验技术的实践经验以及实践经验中发展专家。约瑟夫·洛斯卡尔佐（Joseph Loscalzo）博士是在这些领域拥有30多年心理经验的国际认可的专家，他将在由代谢和肺部疾病的杰出科学家组成的咨询委员会的支持下指导奥尔德姆博士。随着奖励期的进行，Oldham博士将发展成功的R01赠款提交所需的技能。 Oldham博士将在BWH医学系的肺部和重症监护医学部门工作，BWH是位于哈佛医学院社区中心内的一个杰出的科学和心理环境。肺动脉高压影响每百万人为15-50人，肺动脉压力升高，以增加受肺部疾病，心力衰竭和其他疾病影响的数百万的发病率和死亡率。 PAH的代谢异常为这种疾病的急需修饰疗法的发展提供了丰富的潜力。奥尔德姆博士的长期目标是定义PAH基础的代谢发展，并开发针对由此产生的代谢脆弱性的疗法。该应用的总体目的是将L2HG在PAH发病机理中的作用定义为朝着长期目标迈出的第一步。中心假设是L2HG产生通过增加肺血管细胞中促增强的活性氧的产生来支持PAH中的肺血管重塑。该提议的理由是，一旦定义了L2HG代谢与PAH发病机理之间的联系，这些生物化学途径就可以在药理学上靶向，从而导致PAH的新颖和疾病改良疗法。中心假设将通过追求以下特定目的进行检验：（1）使用生化和动力学建模方法确定L2HG代谢，糖酵解和细胞氧化还原态之间的生化联系； （2）确定L2HG代谢对L2HG水平的遗传操纵以及细胞增殖，凋亡和活性氧的产生的遗传操作的影响； （3）确定L2HG代谢在使用转基因的小鼠开发PAH中的作用。这项工作的贡献预计将是对L2HG代谢如何调节细胞氧化还原稳态以支持PAH肺血管重塑的一种机械理解。这项贡献将是重要的，因为它将定义L2HG在正常和解散的代谢中的关键作用，从而增强我们对细胞对缺氧和其他压力源的反应的理解。拟议的研究具有创新性，因为它通过确定L2HG代谢在细胞氧化还原稳态中的重要作用来代表与现状的新事物。这项研究将在细胞内氧化还原信号的研究中开放新的视野。此外，该途径以前尚未与PAH相关，代表了疾病发病机理机械投资的新领域。由于L2HG在任何已知的代谢途径中都不是中间体，因此其代谢可能会为操纵细胞氧化还原状态提供安全且易于处理的实验性和治疗性TAR，这将为这种致命疾病的未来投资提供宝贵的工具。