Sineoculis Homeobox Homolog 1 (Six1) in Pulmonary Fibrosis

肺纤维化中的 Sineoculis 同源框同源物 1 (Six1)

基本信息

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
项目类别：
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

项目摘要

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.

项目概要间质性肺病最常见的表现之一是特发性肺纤维化（IPF），一种慢性、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 180,000 名美国人。亚临床上皮损伤已被确定为 IPF 的核心过程。 IPF 的预后很糟糕，65 岁或以上成年人的中位生存期为 3.8 年。重要的 IPF 治疗的进展包括尼达尼布和吡非尼酮的批准。虽然这些代理是能够在临床上减轻 IPF 肺功能的丧失，但不能完全阻止或逆转进展的疾病。这强调需要确定治疗 IPF 的新疗法。上皮重编程 II 型肺泡细胞 (AEC2) 的增殖是导致 IPF 肺重塑的核心过程。有趣的是，我们有鉴定出一种在 IPF 中上调的新型发育转录因子：Sine Oculis Homeobox Homolog 1（六）及其辅因子眼睛缺失（EYA）-1和2。使用博莱霉素（BLM）诱导的实验模型肺纤维化，我们证明 AEC2 中 SIX1 的缺失抑制了肺纤维化的发展改善肺功能，并且 AEC2 中 SIX1 过度表达导致非典型肺上皮化。采取这些结果共同表明 AEC2 中 SIX1 的升高是肺纤维化的重要途径。初步数据表明该途径的激活促进衰老相关分泌表型的表达 (SASP) 因素和 AEC2 增生，肺纤维化的关键特征。然而，SIX1/EYA 驱动促进这些变革的机制尚未得到充分理解，并将在本提案中受到质疑。