Sineoculis Homeobox Homolog 1 (Six1) in Pulmonary Fibrosis

肺纤维化中的 Sineoculis 同源框同源物 1 (Six1)

• 批准号: 10589121
• 负责人: Harry Karmouty-Quintana
• 金额: $ 51.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589121
• 关键词: Adult; Affect; American; Attenuated; Biological Assay; Bleomycin; Cell Aging; Cell Proliferation; Cell Separation; Cells; Chronic; Cilia; Clinical; Complex; Cre lox recombination system; DNA Damage; Data; Defect; Deposition; Development; Disease; Disease Progression; Drug Approval; Embryo; Epithelial Cells; Epithelium; Etiology; Experimental Models; Extracellular Matrix; Eye; Family; Fibroblasts; Fibrosis; Functional disorder; Genes; Genetic Transcription; Homeobox; Homologous Gene; Human; Hyperplasia; Immunohistochemistry; In Vitro; Inflammatory; Injury; Interstitial Lung Diseases; Link; Lung; Lung Transplantation; Malignant Neoplasms; Mediating; Mediator; Mesenchymal; Messenger RNA; Modeling; Mus; Mutation; Organogenesis; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Pirfenidone; Prevalence; Process; Production; Prognosis; Proliferating; Protein Isoforms; Proteins; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein C; Role; Signal Transduction; Structure of thyroid parafollicular cell; TERF1 gene; Techniques; Telomere Length Maintenance; Testing; Type II Epithelial Receptor Cell; Up-Regulation; age related; alveolar epithelium; alveolar type II cell; autocrine; cofactor; epithelial injury; gain of function; idiopathic pulmonary fibrosis; improved; in vivo; loss of function; lung development; lung injury; member; nintedanib; novel; novel therapeutics; overexpression; paracrine; prevent; pulmonary function; senescence; transcription factor

Project Summary One of the most widespread presentations of Interstitial Lung Disease is Idiopathic Pulmonary Fibrosis (IPF), a chronic, progressive and fatal disease. The prevalence of IPF in the US has increased 2-fold in the last 10 years and it affects ~180,000 Americans. Subclinical epithelial injury has been identified as a central process in IPF. The prognosis of IPF is dire, with a median survival of 3.8 years among adults 65 years or older. Important advances in the therapy of IPF include the approval of nintedanib and pirfenidone. Although these agents are able to clinically attenuate the loss of lung function in IPF, they do not completely halt or reverse the progression of disease. This underscores the need to identify novel therapies for the treatment of IPF. Epithelial reprograming of alveolar type II cells (AEC2) is a central process that leads to lung remodeling in IPF. Intriguingly, we have identified a novel developmental transcription factors that is up-regulated in IPF: Sine Oculis Homeobox Homolog 1 (SIX) and its co-factors eyes absent (EYA)-1 and 2. Using an experimental model of bleomycin (BLM)-induced lung fibrosis, we demonstrate that deletion of SIX1 in AEC2 inhibited the development of lung fibrosis and improved lung function and that SIX1 overexpression in AEC2 results in an atypical lung epithelization. Taken together these results point at elevated SIX1 in AEC2 as an important pathway for lung fibrosis. Preliminary data suggests that activation of this pathway promotes expression of senescent associate secretory phenotype (SASP) factors and hyperplasia of AEC2, key features of lung fibrosis. However, the SIX1/EYA driven mechanisms that promote these changes are not fully understood and will be interrogated in this proposal.

项目摘要 间质性肺疾病最广泛的表现之一是特发性肺纤维化（IPF）， 慢性、进行性和致命性疾病。过去10年，美国IPF的患病率增加了2倍 它影响了大约18万美国人。亚临床上皮损伤已被确定为IPF的中心过程。 IPF的预后很差，65岁或以上成人的中位生存期为3.8年。重要 IPF治疗的进展包括尼达尼布和吡非尼酮的批准。虽然这些代理商 它们能够在临床上减轻IPF的肺功能丧失，但不能完全阻止或逆转进展 疾病。这强调了需要确定治疗IPF的新疗法。上皮重编程 肺泡II型细胞（AEC 2）的凋亡是导致IPF肺重塑的中心过程。有趣的是， 鉴定了一种在IPF中上调的新的发育转录因子：Sine Oculis同源框同源物 1（SIX）及其辅助因子眼缺失（EYA）-1和2。使用博来霉素（BLM）诱导的实验模型， 肺纤维化，我们证明了AEC 2中SIX 1的缺失抑制了肺纤维化的发展， 肺功能改善，并且AEC 2中的SIX 1过表达导致非典型肺上皮形成。采取 这些结果共同指出AEC 2中升高的SIX 1是肺纤维化的重要途径。初步数据 提示该途径的激活促进衰老相关分泌表型的表达， （SASP）因子与AEC 2增生、肺纤维化的关键特征。然而，SIX 1/EYA驱动 促进这些变化的机制尚未得到充分理解，本提案将对此进行探讨。