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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

基本信息

批准号：
9108524
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
项目类别：
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/9108524
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 Chemicals Chemistry Clinical Communities Critical Care Development Disease Doctor of Medicine Doctor of Philosophy Energy Metabolism Environment Enzymes 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 Investigation Investigational Therapies Isocitrate Dehydrogenase K-Series Research Career Programs Kinetics 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 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 Tars Techniques Testing Time Training Training Programs United States National Institutes of Health Universities Vascular Diseases Vascular remodeling Venous Ventricular Woman Work cancer cell career career development cell growth design enantiomer experience genetic manipulation in vivo innovation instructor medical schools member metabolomics mitochondrial membrane mortality novel oxidation pressure programs public health relevance pulmonary arterial hypertension research study response skills stressor therapeutic target therapy development tool transcription factor

项目摘要

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（K 08）提案描述了一个为期五年的学术肺医学职业发展培训计划。首席研究员威廉奥尔德姆医学博士，哲学博士、是布里格姆妇女医院（BWH）和哈佛医学院肺部和重症监护医学部的副医师和医学讲师。他拥有化学和生物化学背景，并在范德比尔特大学NIH医学科学家培训计划成员期间完成了药理学博士研究。他于2012年完成了内科，肺病和重症监护医学的临床培训。他的目标是发展一个成功的职业生涯，作为一个独立资助的医生，科学家调查肺血管疾病的氧化还原代谢。在K 08奖提供的支持和保护时间下，奥尔德姆博士将通过正式课程、独立学习和相关实验技术的实践经验，发展能量代谢、氧化还原生物化学、线粒体生理学和动态建模领域的专业知识。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，他将在由代谢和肺部疾病领域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。随着奖励期的进展，奥尔德姆博士将发展成功提交R 01赠款所需的技能。奥尔德姆博士将在BWH医学系的肺部和重症监护医学部工作，这是一个位于哈佛医学院社区中心的杰出科学和指导环境。肺动脉高压影响每百万人中15-50人，并且肺动脉压力升高导致数百万人的发病率和死亡率增加，更多人受到肺病、心力衰竭和其他病症的影响。PAH中的代谢异常为开发这种疾病急需的疾病修饰疗法提供了丰富的潜力。奥尔德姆博士的长期目标是确定PAH潜在的代谢紊乱，并开发针对由此产生的代谢脆弱性的治疗方法。本申请的总体目标是确定L2 HG在PAH发病机制中的作用，作为实现其长期目标的第一步。中心假设是L2 HG的产生通过增加肺血管细胞中促增殖活性氧的产生来支持PAH中的肺血管重塑。该提议的基本原理是，一旦确定了L2 HG代谢与PAH发病机制之间的联系，就可以靶向这些生化途径，从而产生PAH的新型疾病缓解疗法。将通过追求以下具体目标来检验中心假设：（1）使用生物化学和动力学建模方法来确定L2 HG代谢、糖酵解和细胞氧化还原状态之间的生物化学联系;（2）使用L2 HG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L2 HG代谢对肺血管细胞表型的影响;（3）用转基因小鼠研究L2 HG代谢在PAH发病中的作用。这项工作的贡献，预计将是一个机制的理解，如何L2 HG代谢调节细胞氧化还原稳态，支持肺血管重建的PAH。这一贡献将是重要的，因为它将定义L2 HG在正常和疾病代谢中的关键作用，这将增强我们对缺氧和其他应激源的细胞反应的理解。拟议的研究是创新的，因为它代表了一个新的和实质性的偏离现状，通过定义一个重要的作用，L2 HG代谢在细胞氧化还原稳态。本研究将为细胞内氧化还原信号的研究开辟新的视野。此外，该途径以前与PAH无关，代表了疾病发病机制机制研究的新领域。由于L2 HG不是任何已知代谢途径的中间体，其代谢可能为操纵细胞氧化还原状态提供安全和易处理的实验和治疗目标，这将为这种致命疾病的未来研究提供有价值的工具。