Functions of the Hypoxia-Induced MicroRNA-210 in Pulmonary Vascular Endothelium

缺氧诱导的 MicroRNA-210 在肺血管内皮细胞中的功能

• 批准号: 8074708
• 负责人: Stephen Y Chan
• 金额: $ 13.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8074708
• 关键词: Aconitate Hydratase; Affect; Bioavailable; Biochemical; Biogenesis; Biological Availability; Biology; Blood Vessels; Cardiology; Cell Line; Cell Respiration; Cell physiology; Data; Disease; Down-Regulation; Electron Transport; Electrons; Endothelial Cells; Endothelium; Environment; Enzymes; Fellowship; Future; Gene Targeting; General Hospitals; Generations; Genes; Homeostasis; Human; Hypoxia; Internal Medicine; Iron; Iron Regulatory Protein 1; Laboratories; Leadership; Lung; Massachusetts; Mediator of activation protein; Medical; Mentors; Metabolism; MicroRNAs; Mitochondria; Modeling; Molecular; Molecular Genetics; Molecular Models; Mus; Nitric Oxide; Oxidative Phosphorylation; Oxygen; Pathway interactions; Phenotype; Phosphorylation; Physiological; Plasminogen Activator Inhibitor 1; Postdoctoral Fellow; Principal Investigator; Process; Production; Proteins; Pulmonary Hypertension; Pulmonary vessels; Reactive Oxygen Species; Regulation; Repression; Research; Residencies; Resources; Respiration; Role; Science; Scientist; Stress; Sulfur; Techniques; Time; Training; Training Programs; Vascular Diseases; Vascular Endothelium; base; career; improved; molecular modeling; new therapeutic target; novel; programs; public health relevance; pulmonary function; research study; response; therapeutic target

DESCRIPTION (provided by applicant): A five year training program is proposed to develop a career in academic cardiology with a focus on pulmonary vascular function and disease. The principal investigator is a graduate of the Medical Scientist Training Program and has completed residency training in Internal Medicine and fellowship training in Cardiology (Massachusetts General Hospital, MGH). Dr. Joseph Loscalzo will serve as the primary laboratory mentor and is a recognized expert and scientific leader in vascular biology. He has successfully trained numerous postdoctoral fellows, many of whom have gone on to major scientific and leadership roles in biomedical sciences. An advisory panel of expert medical scientists will also provide further scientific and career guidance. By combining the resources of multiple Harvard-affiliated programs, this training environment is ideal to cultivate a successful research program on which to base a productive future career. The principal investigator has identified the hypoxia-induced microRNA-210 (miR-210) as a novel and essential regulator of mitochondrial metabolism and cellular respiration in hypoxic pulmonary arterial endothelial cells, via repression of the iron-sulfur cluster assembly proteins ISCU1/2. This proposal will interrogate a model whereby control of endothelial-specific phenotypes in the pulmonary vasculature depends critically upon the down-regulation of ISCU1/2 and iron-sulfur clusters by miR-210. Under conditions of normoxia and hypoxia, experiments will entail expression of miR-210 and inhibition of miR-210 in cultured pulmonary arterial endothelial cells as well as in the pulmonary vasculature of murine subjects. Phenotypes will be assessed by a combination of molecular, genetic, biochemical, and biophysical techniques. Proposed experiments listed under "Specific Aims" will elucidate the role of miR-210, ISCU1/2, and iron-sulfur clusters in the regulation of: 1) mitochondrial electron transport; 2) reactive oxygen species flux; and 3) nitric oxide bioavailability. Results will improve our molecular understanding of physiologic and pathophysiologic adaptations in the hypoxic pulmonary vasculature and may point to novel therapeutic targets. PUBLIC HEALTH RELEVANCE: This proposal will define the critical actions of a novel molecule (microRNA-210) in regulating the response to low oxygen exposure in cells that line the blood vessels of the lungs. In doing so, it is expected to improve the current understanding of the mechanisms by which low oxygen conditions affect the pulmonary vessels during normal and disease states and may point to future therapeutic targets.

描述（由申请人提供）：建议开展为期五年的培训计划，以发展学术心脏病学职业，重点关注肺血管功能和疾病。主要研究者是医学科学家培训项目的毕业生，并完成了内科住院医师培训和心脏病学专科培训（麻省总医院，MGH）。 Joseph Loscalzo 博士将担任主要实验室导师，他是血管生物学领域公认的专家和科学领导者。他成功地培养了众多博士后研究员，其中许多人后来在生物医学领域担任重要的科学和领导职务。由医学专家组成的顾问小组还将提供进一步的科学和职业指导。通过结合多个哈佛附属项目的资源，这种培训环境非常适合培养成功的研究项目，为未来富有成效的职业生涯奠定基础。 主要研究人员发现，缺氧诱导的 microRNA-210 (miR-210) 通过抑制铁硫簇组装蛋白 ISCU1/2，成为缺氧肺动脉内皮细胞线粒体代谢和细胞呼吸的新型重要调节剂。该提案将质疑一个模型，通过该模型，肺血管系统中内皮特异性表型的控制关键取决于 miR-210 对 ISCU1/2 和铁硫簇的下调。在常氧和缺氧条件下，实验将需要在培养的肺动脉内皮细胞以及小鼠受试者的肺脉管系统中表达 miR-210 和抑制 miR-210。表型将通过分子、遗传、生物化学和生物物理技术的组合来评估。 “具体目标”下列出的拟议实验将阐明 miR-210、ISCU1/2 和铁硫簇在调节中的作用：1）线粒体电子传递； 2) 活性氧通量； 3) 一氧化氮生物利用度。结果将提高我们对缺氧肺血管系统生理和病理生理适应的分子理解，并可能指出新的治疗靶点。 公共健康相关性：该提案将定义一种新型分子（microRNA-210）在调节肺部血管细胞对低氧暴露反应的关键作用。在此过程中，预计将提高目前对低氧条件在正常和疾病状态下影响肺血管的机制的理解，并可能为未来的治疗目标指明方向。