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

项目摘要 谢伊博士的职业目标是成为一名独立的内科科学家和 对肺纤维化疾病的认识。他完成了肺部和重症监护的临床培训 哈佛大学联合奖学金计划的医学博士，他一直在研究安德鲁博士的肺纤维化 在过去的三年半里，他一直在马萨诸塞州总医院的实验室工作。他们一起工作 在脂类介体溶血磷脂酸(LPA)和鞘氨醇的作用上有了令人兴奋的发现 1-磷酸(S1P)，与肺损伤和纤维化有关。这项研究已发表在《自然医学》杂志和 美国呼吸系统细胞与分子生物学杂志。谢伊博士已被选为他的 在多个国际会议上研究S1P在肺纤维化中的作用，并获得 第六届呼吸系统疾病青年研究人员论坛基础科学类。 谢伊博士有一个理想的环境来进行这项提案中概述的研究， 追求他的职业目标。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，他已经 为谢伊博士提供了到目前为止他职业生涯中杰出的导师，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性。谢伊医生有权接触到所有的身体和 麻省理工学院免疫与炎症性疾病中心(CIID)和肺部的智力资源 和重症监护病房(PCCU)，并得到CIID、PCCU和MGH部门的全力支持 医学。他还组建了一个由非常成功的科学家组成的强大的顾问委员会。 他们致力于协助谢伊博士的研究工作和职业发展。 我们已经发现，S1P受体S1P1的拮抗作用显著恶化了肺血管 博莱霉素攻击后小鼠的渗漏和纤维化。我们的总体假设是(1)S1P-S1P1信号转导 内皮细胞保护肺损伤后血管渗漏和(2)减少血管渗漏保护 通过限制血浆凝血因子的外溢来抗损伤所致的肺纤维化 在空气中激活凝血酶/PAR-1信号。这项建议的第一个目标是确定 通过评估内皮细胞S1P-S1P1信号在肺损伤和纤维化调节中的重要性 可诱导的内皮特异性S1P1缺陷小鼠对博莱霉素后血管渗漏和纤维化的易感性 肺损伤。这项建议的第二个目标是确定血管泄漏和血管泄漏之间的机制联系。 纤维化，通过研究S1P1拮抗剂是否有能力加剧纤维化反应 博莱霉素肺损伤在PAR-1缺陷小鼠中被消除。这项提案的第三个目标是确定 提高S1P水平是否可以预防肺损伤和纤维化，我们将通过以下方式实现这一点 将表达S1P产生酶神经鞘氨酸激酶1的腺病毒基因转移载体 测定小鼠肺组织对博莱霉素肺损伤后血管渗漏和纤维化的敏感性。

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.