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

描述（由申请人提供）：Shea博士的职业目标是成为一名独立的医生-科学家和了解纤维化肺病的领导者。他在哈佛联合奖学金计划中完成了肺部和重症监护医学的临床培训，过去三年半他一直在马萨诸塞州总医院的Andrew Tager博士实验室研究肺纤维化。他们的共同工作导致了关于脂质介质溶血磷脂酸（LPA）和1-磷酸鞘氨醇（S1 P）在肺损伤和纤维化中的作用的令人兴奋的发现。这项工作已发表在《自然医学》和《美国呼吸细胞和分子生物学杂志》上。Shea博士被选中在多个国际会议上介绍他对肺纤维化中S1 P的研究，并在第六届年度呼吸系统疾病青年研究者论坛上获得基础科学类一等奖。 Shea博士有一个理想的环境来执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Tager博士的指导，Tager博士是一位杰出的科学家，他在Shea博士的职业生涯中为Shea博士提供了出色的指导，并真正致力于促进Shea博士作为科学家的成长和独立性。Shea博士可以使用MGH免疫学和炎症疾病中心（CIID）和肺部和重症监护室（PCCU）的所有物理和智力资源，以及CIID，PCCU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Shea博士的研究工作和职业发展。 我们已经发现，拮抗S1 P受体，S1 P1，显着恶化肺血管渗漏和肺纤维化后，博莱霉素的挑战。我们的总体假设是：（1）内皮细胞上的S1 P-S1 P1信号传导可防止肺损伤后的血管渗漏，（2）减少血管渗漏可通过限制血浆凝血因子的外渗以及随后的凝血酶/PAR-1信号传导在气隙内的激活来防止损伤诱导的肺纤维化。该提案的第一个目的是通过评估可诱导的内皮特异性S1 P1缺陷小鼠对博来霉素肺损伤后血管渗漏和纤维化的易感性，确定内皮S1 P-S1 P1信号传导对肺损伤和纤维化调节的重要性。该建议的第二个目的是通过研究PAR-1缺陷小鼠中S1 P1拮抗作用是否能够消除对博莱霉素肺损伤的纤维化反应，来确定血管渗漏和纤维化之间的机制联系。该提案的第三个目的是确定S1 P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S1 P产生酶鞘氨醇激酶1的腺病毒基因转移载体递送到小鼠肺中来实现，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。 公共卫生相关性：特发性肺纤维化（IPF）是一种病因不明的疾病，其特征是肺部进行性瘢痕形成，导致肺功能受损、呼吸困难和最终死亡。诊断后的中位生存期仅约3年，并且没有已被证明有效减缓该疾病进展或预防死亡的疗法。我们相信，本申请中提出的实验将为脂质介质1-磷酸鞘氨醇（S1 P）在肺纤维化发展中的作用提供新的见解，并确定靶向S1 P通路是否有可能成为IPF这一毁灭性疾病的新治疗策略。

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.