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: 8027932
• 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/8027932
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by progressive scar formation in the lungs, leading to impaired lung function, difficulty breathing, and eventual death. The median survival after diagnosis is only approximately 3 years, and there are no therapies which have proven to be effective at slowing the progression of this disease or preventing mortality. We believe the experiments proposed in this application will provide new insights into the role of the lipid mediator, sphingosine 1- phosphate (S1P), in the development of pulmonary fibrosis, and determine whether targeting the S1P pathway has the potential to be a novel therapeutic strategy for the devastating disease of IPF.

描述（由申请人提供）：谢伊博士的职业目标是成为一名独立的内科科学家，并在纤维化肺部疾病的理解方面处于领先地位。他在哈佛大学联合奖学金项目中完成了肺部和重症监护医学的临床培训，在过去的三年半里，他一直在马萨诸塞州总医院安德鲁·塔格博士的实验室研究肺纤维化。他们的共同工作导致了脂质介质溶血磷脂酸（LPA）和鞘氨醇1-磷酸（S1P）在肺损伤和纤维化中的作用的令人兴奋的发现。这项研究发表在《自然医学》和《美国呼吸细胞与分子生物学杂志》上。Shea博士曾在多个国际会议上被选中介绍他在肺纤维化中的S1P研究，并在第六届年度呼吸系统疾病青年研究人员论坛上获得基础科学类一等奖。谢伊博士拥有一个理想的环境，可以在其中进行本提案中概述的研究并追求他的职业目标。他将继续接受塔格博士的指导，塔格博士是一位杰出的科学家，在谢伊博士的职业生涯中为他提供了出色的指导，他真诚地致力于培养谢伊博士作为一名科学家的成长和独立。Shea博士可以使用MGH免疫和炎症疾病中心（CIID）和肺部和重症监护病房（pcccu）的所有体力和智力资源，并得到CIID、pcccu和MGH医学部的全力支持。他还组建了一个强大的咨询委员会，由非常成功的科学家组成，他们致力于协助谢伊博士的研究努力和职业发展。我们发现S1P1受体的拮抗作用显著加重了博莱霉素刺激后小鼠肺血管渗漏和纤维化。我们的总体假设是：(1)内皮细胞上的S1P-S1P1信号可以防止肺损伤后的血管泄漏；(2)通过限制血浆凝血因子的外渗以及随后在空气空间内凝血酶/PAR-1信号的激活，减弱血管泄漏可以防止损伤诱导的肺纤维化。本研究的第一个目的是通过评估诱导型、内皮特异性s1p1缺陷小鼠在博来霉素肺损伤后对血管渗漏和纤维化的易感性，来确定内皮S1P-S1P1信号在肺损伤和纤维化调节中的重要性。本研究的第二个目的是通过研究par1缺陷小鼠中S1P1拮抗剂加剧博来霉素肺损伤纤维化反应的能力是否被削弱，来确定血管泄漏与纤维化之间的机制联系。本研究的第三个目的是确定S1P水平的增加是否可以防止肺损伤和纤维化，我们将通过将表达S1P产生酶鞘氨醇激酶1的腺病毒基因转移载体传递到小鼠肺中，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。