The Role of Sphingosine 1-Phosphate in Lung Injury and Fibrosis

1-磷酸鞘氨醇在肺损伤和纤维化中的作用

• 批准号: 8389870
• 负责人: Barry S. Shea
• 金额: $ 13.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-08 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389870
• 关键词: Adenoviruses; Advisory Committees; Alveolar; American; Attenuated; Award; Basic Science; Biological Process; Bleomycin; Blood Coagulation Factor; Blood Vessels; Breathing; Categories; Cellular biology; Cessation of life; Cicatrix; Clinical; Coagulation Process; Commit; Complex; Critical Care; Development; Diagnosis; Disease; Disease Progression; Endothelial Cells; Environment; Enzymes; Equilibrium; Etiology; Extravasation; Fellowship Program; Fibrosis; Fostering; General Hospitals; Generations; Goals; Growth; Hamman-Rich syndrome; Immunology; Inflammatory; Injury; International; Journals; Laboratories; Lead; Link; Lung; Lung diseases; Lysophospholipids; Massachusetts; Mediating; Medicine; Mentors; Mentorship; Metabolism; Molecular Biology; Mus; Nature; PAR-1 Receptor; Pathway interactions; Physicians; Plasma; Play; Predisposition; Prize; Publishing; Pulmonary Fibrosis; Regulation; Research; Research Personnel; Resolution; Resources; Respiratory physiology; Role; SPHK1 enzyme; Scientist; Series; Signal Transduction; Sphingosine-1-Phosphate Receptor; Structure; Testing; Therapeutic; Thrombin; Time; Training; Work; career; career development; cell type; design; edg-1 Protein; gene transfer vector; in vivo; indium-bleomycin; injured; insight; lipid mediator; lung development; lung injury; lysophosphatidic acid; mortality; mouse model; novel; novel therapeutics; prevent; research study; respiratory; response; response to injury; restoration; sphingosine 1-phosphate; symposium

Project Summary Dr. Shea's career goal is to become an independent physician-scientist and a leader in the understanding of fibrotic lung diseases. He completed his clinical training in Pulmonary and Critical Care Medicine in the Harvard Combined Fellowship Program, and he has been studying lung fibrosis in Dr. Andrew Tager's laboratory at Massachusetts General Hospital for the past three and a half years. Their work together has led to exciting discoveries on the roles of the lipid mediators, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), in lung injury and fibrosis. This work has been published in Nature Medicine and the American Journal of Respiratory Cell and Molecular Biology. Dr. Shea has been selected to present his research on S1P in lung fibrosis at several international conferences, and he was awarded first prize in the basic science category at the Sixth Annual Respiratory Disease Young Investigators' Forum. Dr. Shea has an ideal environment in which to perform the research outlined in this proposal and pursue his career goals. He will continue to be mentored by Dr. Tager, an exceptional scientist who has provided Dr. Shea with outstanding mentorship thus far in his career, and who is genuinely committed to fostering Dr. Shea's growth and independence as a scientist. Dr. Shea has access to all of the physical and intellectual resources of the MGH Center for Immunology and Inflammatory Diseases (CIID) and Pulmonary and Critical Care Unit (PCCU), and the full support of the CIID, the PCCU, and the MGH Department of Medicine. He has also assembled a formidable advisory committee composed of highly successful scientists who are committed to assisting Dr. Shea in his research endeavors and career development. We have found that antagonism of the S1P receptor, S1P1, dramatically worsened pulmonary vascular leak and fibrosis after bleomycin challenge in mice. Our overall hypotheses are that (1) S1P-S1P1 signaling on endothelial cells protects against vascular leak after lung injury and (2) attenuating vascular leak protects against injury-induced lung fibrosis by limiting the extravasation of plasma clotting factors, and the subsequent activation of thrombin/PAR-1 signaling, within the airspaces. The first aim of this proposal is to determine the importance of endothelial S1P-S1P1 signaling to the regulation of lung injury and fibrosis, by assessing the susceptibility of inducible, endothelial-specific S1P1-deficient mice to vascular leak and fibrosis after bleomycin lung injury. The second aim of this proposal is to determine the mechanistic link between vascular leak and fibrosis, by investigating whether the ability of S1P1 antagonism to exacerbate the fibrotic response to bleomycin lung injury is abrogated in PAR-1 deficient mice. The third aim of this proposal is to determine whether augmentation of S1P levels can protect against lung injury and fibrosis, which we will accomplish by delivering an adenovirus gene transfer vector expressing the S1P-producing enzyme, sphingosine kinase 1, to the lungs of mice, then determining their susceptibility to vascular leak and fibrosis after bleomycin lung injury.

项目摘要 Shea博士的职业目标是成为一名独立的物理学家和科学家， 了解纤维化肺疾病。他完成了肺部和重症监护的临床培训 医学在哈佛联合奖学金计划，他一直在研究肺纤维化博士安德鲁 在过去的三年半里，塔格在马萨诸塞州总医院的实验室工作。他们的工作 导致了令人兴奋的发现的作用，脂质介质，溶血磷脂酸（LPA）和鞘氨醇 1-磷酸盐（S1 P）在肺损伤和纤维化中的作用。这项工作已发表在《自然医学》和《 美国呼吸细胞与分子生物学杂志。谢伊博士被选中来介绍他的 他在多个国际会议上研究了S1 P在肺纤维化中的作用，并获得了一等奖。 第六届呼吸系统疾病青年研究者论坛的基础科学类别。 Shea博士有一个理想的环境来进行本提案中概述的研究， 追求自己的职业目标。他将继续接受泰格博士的指导，泰格博士是一位杰出的科学家， 为Shea博士提供了迄今为止在他职业生涯中出色的指导，并且真正致力于 培养谢伊博士作为一名科学家的成长和独立性谢伊医生能接触到所有的 MGH免疫学和炎症性疾病中心（CIID）和肺 和重症监护室（PCCU），以及CIID，PCCU和MGH部门的全力支持， 药他还组建了一个由非常成功的科学家组成的强大的咨询委员会 他们致力于协助Shea博士的研究工作和职业发展。 我们已经发现，S1 P受体S1 P1的拮抗作用显著恶化了肺血管 在小鼠中博来霉素攻击后渗漏和纤维化。我们的总体假设是：（1）S1 P-S1 P1信号传导在 内皮细胞保护肺损伤后的血管渗漏;（2）减少血管渗漏保护 通过限制血浆凝血因子的外渗来对抗损伤诱导的肺纤维化， 凝血酶/PAR-1信号传导的激活。本建议的第一个目的是确定 通过评估内皮细胞S1 P-S1 P1信号传导对肺损伤和纤维化调节的重要性， 诱导型内皮特异性S1 P1缺陷小鼠对博来霉素治疗后血管渗漏和纤维化易感性 肺损伤该建议的第二个目的是确定血管渗漏和 纤维化，通过研究S1 P1拮抗作用是否有能力加剧纤维化反应 博来霉素肺损伤在PAR-1缺陷小鼠中被消除。本建议的第三个目的是确定 增加S1 P水平是否可以防止肺损伤和纤维化，我们将通过以下方法来实现这一点： 递送表达S1 P产生酶鞘氨醇激酶1的腺病毒基因转移载体， 小鼠的肺，然后确定它们对博来霉素肺损伤后血管渗漏和纤维化的易感性。