Syndecan-1 regulation of lung fibrosis

摘要 这项提议是为了将Tanyalak Parimon，M.D.的职业发展成为一名独立的内科科学家 专注于肺纤维化的基础/转译研究。PI将由Peter Chen，M.D.作为共同导师，他 在Syndecan-1和Dolores Di Vizio，M.D.，Ph.D.的肺部生物学方面有既定的研究计划 是细胞外小泡生物学方面的领先专家。综合培训计划将包括实验室- 基础研究、说教讲座、课程作业和研讨会、助学金、科学会议(内部 和外部)，以及由包括共同导师的科学咨询委员会提供的职业指导。有了这个 建议，我将有机会继续学习和拓宽我的研究技能和知识 肺损伤和修复的机制，以肺纤维化和细胞外小泡(EVS)生物学为重点。 此外，我将利用领先的呼吸系统研究和电动汽车的科学和技术知识 在雪松-西奈和大洛杉矶地区的专家进行我的研究和我的培训 成为一名独立的内科医生兼科学家。对于研究提案，我将进一步了解 肺纤维化发病机制与长期目标确定细胞靶点的新研究(S) 成为肺纤维化的治疗选择，并成为该领域领先的独立研究人员。Syndecan-1， 一种主要在上皮细胞上表达的跨膜型硫酸乙酰肝素蛋白多糖，在 上皮细胞损伤和修复，我证明了它在肺纤维增生性疾病中起着核心作用。这个 我将探索并得到我的初步数据支持的机制是Syndecan-1改变了miRNA 肺泡II型上皮细胞(AECII)分泌的胞外小泡(EVS)内的分布 肺微环境中的纤维化改变。这些发现导致了Syndecan-1的假设 通过控制EVS中的抗纤维化miRNAs包装促进肺纤维化，从而重塑肺 促进纤维增殖的微环境。在这个职业发展奖下，我建议测试一下 有三个具体目的的假说：1)确定syndecan-1调节miRNA包装的机制 2)阐明Syndecan-1如何通过促进AECII衰老促进纤维化；以及3)评估如何 Syndecan-1控制纤维化上皮源性EVS，以促进纤维增殖。

ABSTRACT This proposal is for the career development of Tanyalak Parimon, M.D., into an independent physician-scientist focused on basic/translational research in lung fibrosis. The PI will have as co-mentors Peter Chen, M.D., who has an established research program in the lung biology of syndecan-1 and Dolores Di Vizio, M.D., Ph.D., who is a leading expert in extracellular vesicle biology. The comprehensive training program will include laboratory- based research, didactic lectures, coursework and workshop, grantsmanship, scientific conferences (internal and external), and career guidance by a scientific advisory committee that includes the co-mentors. With this proposal, I will have the opportunity to continue to learn and broaden my research skills and knowledge of mechanisms of lung injury and repair with a focus in lung fibrosis and extracellular vesicle (EVs) biology. Additionally, I will leverage the scientific and technical knowledge of leading respiratory research and EVs experts at Cedars-Sinai and the greater Los Angeles area in performing my research and in my training to become an independent physician-scientist. For the research proposal, I will be furthering our understanding into mechanisms of lung fibrosis pathogenesis with the long-term goal to identify the cellular target(s) for a novel therapeutic option for lung fibrosis and to become a leading independent investigator in this field. Syndecan-1, a transmembrane heparan sulfate proteoglycan primarily expressed on epithelial cells, has extensive roles in epithelial cells injury and repair, and I show that it has a central role in lung fibroproliferative diseases. The mechanism that I will explore and is supported by my preliminary data is that syndecan-1 altered the miRNA profile within extracellular vesicles (EVs) secreted by the alveolar epithelial type II cells (AECII) to promote fibrogenic changes within the lung microenvironment. These findings led to the hypothesis that syndecan-1 promotes lung fibrosis by controlling anti-fibrotic miRNAs packaging in EVs, thereby reshaping the lung microenvironment to promote fibroproliferation. Under this career development award, I propose to test the hypothesis with three specific aims: 1) Identify mechanisms by which syndecan-1 regulates miRNA packaging into EVs; 2) Elucidate how syndecan-1 facilitates fibrosis by promoting AECII senescence; and 3) Evaluate how syndecan-1 controls fibrotic epithelial-derived EVs to augment fibroproliferation.