Mitochondrial DNA and TLR9 in Pulmonary Fibrosis

肺纤维化中的线粒体 DNA 和 TLR9

基本信息

批准号：
10668259
负责人：
Changwan Ryu
金额：
$ 16.79万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668259
关键词：
Acceleration Actins Activities of Daily Living Adult Area Biological Assay Biomedical Engineering Biometry Bleomycin Bronchoalveolar Lavage Career Mobility Cells Cellular Assay Chronic lung disease Clinical Collagen Computational Biology Dedications Department chair Deposition Development Disease Dose Endosomes Environment Experimental Models Exposure to Extracellular Matrix Fellowship Fibroblasts Fibrosis Funding Genes Genomics Goals Grant Harvest Human Immune system Immunologic Receptors In Vitro Inflammation Inflammatory Inhalation Interstitial Lung Diseases Laboratories Longitudinal cohort Lung Lung Transplantation Measurement Mediating Mentors Mentorship Methods Mitochondria Mitochondrial DNA Modeling Molecular Mus Myofibroblast Natural Immunity Nature Outcome Pathogenesis Patients Pattern Pharmaceutical Preparations Phenocopy Phenotype Physicians Plasma Play Process Pulmonary Fibrosis Radiation Reporter Research Research Personnel Research Project Grants Role Scientist Secondary to Smooth Muscle Structure of parenchyma of lung TGFB1 gene TLR9 gene Testing Time Toxic Environmental Substances Training Transforming Growth Factor-Beta Overexpression Work alveolar epithelium antifibrotic treatment career career development cell injury cohort combat cost curative treatments drug development epithelial injury extracellular fibrotic lung fibrotic lung disease idiopathic pulmonary fibrosis immune activation in vitro Model in vivo inhibitor insight mechanotransduction metabolic profile mortality novel novel therapeutics overexpression polyacrylamide hydrogels response response to injury side effect single-cell RNA sequencing translational medicine translational study

项目摘要

PROJECT SUMMARY Candidate: My long-term career goal is to develop a successful academic career and become an independently funded physician-scientist focused on the study of innate immunity in idiopathic pulmonary fibrosis (IPF). Under the guidance of my mentor and research advisors, I have received training in laboratory-based assays, in vitro models of IPF, translational medicine, and biostatistics. I have proposed career development activities that will allow me to continue this training, but also develop unique expertise that is distinct from my mentor in the areas of (1) innate immunity and (2) computational biology. Mentors and Environment: I will be mentored by Dr. Erica Herzog, a globally renowned IPF investigator who has studied the immunopathogensis of fibrosis with an extremely impressive track record of successful mentees. My advisors include Dr. Naftali Kaminski, a well-known IPF investigator whose visionary methods in the genomic profiling of fibrotic lung disease have revolutionized the field; Dr. Wajahat Mehal, who has been lauded for his work with mitochondrial DNA (mtDNA) and Toll-Like Receptor 9 (TLR9) in the development of fibrosis; Dr. Min-Jong Kang, an expert in mitochondrial innate immunity in chronic lung disease; and Dr. Anjelica Gonzalez, who has developed novel methods in bioengineering for ex vivo modeling of the fibrotic microenvironment. My department Chair (Dr. Gary Desir) has assured me that at least 75% of my time will be dedicated to my career development, and he and my Section Chief (Dr. Kaminski) have detailed their commitment. Mentored Research Project: The pathogenesis of IPF involves the uncontrolled accumulation of activated myofibroblasts, which arise in response to TGFβ1 mediated interactions with the stiff fibrotic lung microenvironment. The innate immune receptor TLR9, which recognizes and responds to mtDNA derived from injured cells, has been shown to have a significant role in mediating this process. We showed that mtDNA is released by TGFβ1-stimulated and stiffness-induced normal human lung fibroblasts, where it induces myofibroblast transformation in a manner that phenocopies fibroblasts harvested from the IPF lung. In the clinical setting, mtDNA concentrations are elevated in the plasma of IPF subjects, where it displays a robust association with all-cause mortality in two independent cohorts. Our subsequent studies reveal that mice deficient in TLR9 are protected from fibrosis caused by lung specific overexpression of the bioactive form of the human TGFβ1 gene and by repetitive administration of low-dose inhaled bleomycin. While exciting, however, these studies are limited by not having determined whether mtDNA-induced fibroblast activation requires TLR9, whether TLR9’s fibrosis promoting effects are mediated through fibroblasts in vivo, and the nature of the mtDNA-TLR9 relationship in IPF. Because elucidation of these questions might substantially impact our understanding of pulmonary fibrosis, this K08 application proposes a state-of-the-art set of translational studies to test the hypothesis that mtDNA-TLR9 interaction drives fibroblast activation and fibrosis in the adult lung.

项目摘要候选人：我的长期职业目标是发展成功的学术职业并成为独立的职业生涯资助的身体科学家专注于研究特发性肺纤维化（IPF）中先天免疫的研究。在下面我的心理和研究顾问的指导，我接受了实验室测定的培训，体外 IPF，转化医学和生物统计学的模型。我提出了职业发展活动允许我继续进行此培训，但也发展独特的专业知识，这与我在该领域的导师不同（1）先天免疫和（2）计算生物学。导师和环境：我将由Erica博士指导赫尔佐格（Herzog）是一位全球知名的IPF研究者成功月经的最令人印象深刻的记录。我的顾问包括著名的Naftali Kaminski博士 IPF研究者的纤维性肺疾病基因组分析中有远见的方法彻底改变了领域； Wajahat Mehal博士因与线粒体DNA（mtDNA）和类似Toll一样的工作而受到称赞受体9（TLR9）在纤维化发展中；线粒体先天免疫专家Min-Jong Kang博士在慢性肺部疾病中；和Anjelica Gonzalez博士，他为EX开发了新颖的方法纤维化微环境的体内建模。我的部门主席（Gary Desir博士）认为我在我至少有75％的时间将致力于我的职业发展，他和我的部门负责人（Kaminski博士）已经详细介绍了他们的承诺。指导研究项目：IPF的发病机理涉及激活的肌纤维细胞的不受控制的积累，这是对TGFβ1介导的相互作用而产生的与僵硬的纤维化肺微环境。固有的免疫受体TLR9，认可并做出回应源自受伤细胞的mtDNA，已显示在介导该过程中具有重要作用。我们表明mtDNA是由TGFβ1刺激和刚度诱导的正常人肺成纤维细胞释放的，它以从IPF收获的表纤维细胞的方式诱导肌纤维细胞转换肺。在临床环境中，MTDNA浓度在IPF受试者的血浆中升高与两个独立人群中的全因死亡率有牢固的关联。我们随后的研究表明 TLR9中特异性的小鼠受到生物活性形式特异性过表达引起的纤维化的保护人类TGFβ1基因和低剂量遗传性博来霉素的重复施用。虽然令人兴奋，但但是，这些研究受到限制，因为没有确定mtDNA诱导的成纤维细胞激活需要TLR9，是否通过体内成纤维细胞介导TLR9的纤维化促进作用，并且性质 IPF中的mtDNA-TLR9关系。因为阐明这些问题可能会大大影响我们的理解肺纤维化，此K08应用提出了一组最先进的翻译研究为了测试MTDNA-TLR9相互作用驱动成年肺的成纤维细胞激活和纤维化的假设。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Occupational and environmental exposures in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study.

Alpha-1 抗胰蛋白酶缺乏症和结节病基因组研究 (GRADS) 研究中的职业和环境暴露。

DOI：
10.1016/j.rmed.2022.106923
发表时间：
2022
期刊：
Respiratory medicine
影响因子：
4.3
作者：
Ryan,SarahM;Mroz,MargaretM;Herzog,EricaL;Ryu,Changwan;Fingerlin,TashaE;Maier,LisaA;Gulati,Mridu
通讯作者：
Gulati,Mridu

A 50-Year-Old Woman With Limited Scleroderma Presenting With Shortness of Breath.

一名 50 岁女性，患有局限性硬皮病，表现为呼吸短促。