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（由申请人提供）：NIH 指导临床科学家研究职业发展奖 (K08) 提案描述了学术肺医学职业发展的五年培训计划，该项目的首席研究员是医学博士 William Oldham。他是布莱根妇女医院 (BWH) 和哈佛医学院肺科和重症监护医学科的副医师和医学讲师。作为范德比尔特大学 NIH 医学科学家培训项目的成员，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。他的目标是作为一名独立的医生发展成功的职业生涯。在 K08 奖提供的支持和保护时间下，Oldham 博士将在能量代谢、氧化还原生物化学、 Joseph Loscalzo 博士是这些领域的国际公认专家，拥有 30 多年的指导经验，他将在线粒体生理学和动态建模方面从正式课程、独立研究和相关实验技术的实践经验中获得指导。一个由代谢和肺部疾病领域的杰出科学家组成的咨询委员会，随着奖励期限的推移，奥尔德姆博士将培养成功提交 R01 资助所需的技能。奥尔德姆博士将在肺科和重症监护医学部门工作。系BWH 的医学是哈佛医学院社区中心的一个出色的科学和指导环境，每百万人中有 15-50 人患有肺动脉高压，肺动脉压力升高导致数百万人受肺病影响的发病率和死亡率增加。肺动脉高压 (PAH) 的代谢异常为开发这种疾病急需的疾病治疗方法提供了丰富的潜力，Oldham 博士的长期目标是确定肺动脉高压 (PAH) 背后的代谢紊乱。该应用的总体目标是确定 L2HG 在 PAH 发病机制中的作用，这是实现其长期目标的第一步，其中心假设是 L2HG 的产生支持肺血管重塑。该提案的基本原理是，一旦确定了 L2HG 代谢与 PAH 发病机制之间的联系，就可以在药理学上靶向这些生化途径。将通过追求以下具体目标来检验中心假设：(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状态之间的生化联系； ) ) 使用 L2HG 水平的遗传操作和细胞增殖、凋亡和活性氧产生的读数来确定 L2HG 代谢对肺血管细胞表型的影响；以及 (3) 确定 L2HG 代谢在肺血管细胞表型中的作用；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肺血管重塑的机制理解。这一贡献将是重要的，因为它将定义关键作用。这项研究具有创新性，因为它定义了重要的作用，代表了对L2HG在正常和患病代谢中的新的实质性偏离。这项研究将为细胞内氧化还原信号传导的研究开辟新的视野，并且由于 L2HG 不是一种疾病发病机制，因此该途径代表了疾病发病机制的新领域。作为任何已知代谢途径的中间体，其代谢可以为操纵细胞氧化还原状态提供安全且易于处理的实验和治疗目标，这将为未来研究这种致命疾病提供有价值的工具。