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：
10371174
负责人：
Harry Karmouty-Quintana
金额：
$ 52.04万
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/10371174
关键词：
Adult Affect American Attenuated Biological Assay Bleomycin Cell Aging Cell Proliferation Cells Chronic Cilia Clinical Complex Cre lox recombination system DNA Damage Data Defect Deposition Development Disease Disease Progression Drug Approval Embryo Epithelial Epithelial Cells 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 of activation protein Mesenchymal Messenger RNA Modeling Mus Mutation Organogenesis Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Pirfenidone Prevalence Process Production Prognosis Proteins Pulmonary Fibrosis Pulmonary Surfactant-Associated Protein C Resort Role Short Interspersed Nucleotide Elements 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 epithelial injury fibrosing agent 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），A 慢性，进行性和致命疾病。在过去的10年中，美国IPF的患病率增加了2倍它影响了约18万美国人。亚临床上皮损伤已被确定为IPF中的中心过程。 IPF的预后很可怕，在65岁以上的成年人中，中位生存期为3.8岁。重要的 IPF治疗的进步包括批准Nintedanib和Pirfenidone。虽然这些代理是能够临床减弱IPF中肺功能的丧失，它们不会完全停止或逆转进展疾病。这强调了确定IPF治疗的新型疗法的需求。上皮重编程肺泡II型细胞（AEC2）的中心过程，导致IPF中的肺重塑。有趣的是，我们有确定了一个新的发育转录因子，该因子在IPF中被上调：正弦Oculis homeobox同源物 1（六）及其共同因素的眼睛不存在（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AEC2中SIX1的缺失抑制了肺纤维化的发展和改善的肺功能和AEC2中的SIX1过表达导致非典型的肺上皮化。拍摄这些结果共同指出，在AEC2中，Six1升高是肺纤维化的重要途径。初步数据表明这种途径的激活促进了衰老分泌表型的表达（SASP）AEC2的因子和增生，这是肺纤维化的关键特征。但是，六1/eya驱动促进这些变化的机制尚未完全理解，并将在此提案中受到审问。