Syndecan-1 regulation of lung fibrosis

Syndecan-1 对肺纤维化的调节

• 批准号: 10434703
• 负责人: Tanyalak Parimon
• 金额: $ 17.07万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-05 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434703
• 关键词: 3-Dimensional; Advisory Committees; Area; Attenuated; Biogenesis; Biology; Bleomycin; Cardiac; Cell Aging; Cell Communication; Cell surface; Cells; Complex; Data; Deposition; Disease; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Endosomes; Epithelial; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibrosis; Goals; Growth Factor; Heparan Sulfate Proteoglycan; Homeostasis; Human; In Vitro; Investigation; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Learning; Ligand Binding; Liver; Los Angeles; Lung; Lung diseases; Lysosomes; Mediating; Membrane Microdomains; Mentors; MicroRNAs; Mus; Organoids; Pathogenesis; Pathway interactions; Phenotype; Physicians; Play; Process; Profibrotic signal; Progressive Disease; Proteoglycan; Pulmonary Fibrosis; Regulation; Reporting; Research; Research Personnel; Research Proposals; Role; Scientist; Signal Pathway; Sorting - Cell Movement; Stimulus; System; Testing; Training; Training Programs; Transforming Growth Factor beta; Translational Research; Type II Epithelial Receptor Cell; Vocational Guidance; Wild Type Mouse; alveolar epithelium; base; career development; cell type; cellular targeting; chemokine; curative treatments; extracellular vesicles; idiopathic pulmonary fibrosis; in vivo; injured; injury and repair; lectures; lung injury; novel; novel therapeutic intervention; novel therapeutics; overexpression; programs; receptor; respiratory; response; senescence; skills; symposium; syndecan; trafficking

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.

抽象的 该提议是针对医学博士Tanyalak Parimon的职业发展，成为一名独立的医师科学家 专注于肺纤维化的基本/翻译研究。 PI将担任M.D.的彼得·陈（Peter Chen） 拥有Syndecan-1肺生物学和DoRores Di Vizio博士学位的研究计划， 是细胞外囊泡生物学领域的领先专家。综合培训计划将包括实验室 - 基于研究，教学讲座，课程和讲习班，授予技巧，科学会议（内部 和外部），以及包括联席会员在内的科学咨询委员会的职业指导。与此 提案，我将有机会继续学习和扩大我的研究技能和知识 肺损伤和修复机制，重点是肺纤维化和细胞外囊泡（EV）生物学。 此外，我将利用领先的呼吸研究和电动汽车的科学和技术知识 Cedars-Sinai和大洛杉矶地区的专家在进行我的研究和培训中 成为独立的医师科学家。对于研究建议，我将使我们的理解发展到 肺纤维化发病机理的机制具有长期目标，以识别新型细胞靶标的细胞靶标 肺纤维化的治疗选择，并成为该领域领先的独立研究者。 Syndecan-1， 主要在上皮细胞上表达的跨膜肝硫酸盐蛋白聚糖在 上皮细胞损伤和修复，我表明它在肺纤维增生性疾病中具有核心作用。这 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 由肺泡上皮II型细胞（AECII）分泌的细胞外囊泡（EV）内的特征 肺微环境内的纤维化变化。这些发现导致了syndecan-1的假设 通过控制电动汽车中的抗纤维化miRNA包装来促进肺纤维化，从而重塑肺 微环境可促进纤维增殖。根据这个职业发展奖，我建议 具有三个特定目的的假设：1）确定syndecan-1调节miRNA包装的机制 进入电动汽车； 2）阐明Syndecan-1如何通过促进AECII衰老来促进纤维化； 3）评估如何 Syndecan-1控制纤维化上皮衍生的电动汽车以增加纤维增殖。