Functional Role of HIF-PHDs in ARDS

HIF-PHD 在 ARDS 中的功能作用

• 批准号: 10718267
• 负责人: Holger K. Eltzschig
• 金额: $ 70.93万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718267
• 关键词: 2019-nCoV; ACE2; Acute Respiratory Distress Syndrome; Address; Adenosine; Alveolar; Anti-Inflammatory Agents; Attenuated; Binding Sites; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19/ARDS; Clinical Trials; Doctor of Philosophy; Exposure to; Feedback; Foundations; Genetic; Genetic Models; Genetic Transcription; Goals; HIF1A gene; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Individual; Infection; Inflammation; Inflammatory Response; Injury; K-18 conjugate; Laboratories; Lung; Lung infections; Mechanical ventilation; Mediating; MicroRNAs; Minor; Modeling; Molecular; Morbidity - disease rate; Mus; Mutation; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Perioperative; Prevention; Protein Isoforms; Pseudomonas aeruginosa; Regulation; Repression; Role; SARS-CoV-2 infection; Sampling; Sepsis; Signal Transduction; Therapeutic; Untranslated Regions; Virus; alveolar epithelium; carbohydrate metabolism; design; experience; genetic approach; in vivo; in vivo Model; lung development; lung injury; mortality; mouse model; overexpression; pathogen; pharmacologic; protective effect; response; stressor; transcription factor; ventilation

PROJECT SUMMARY This application aims to investigate the regulation of hypoxia-inducible factor HIF1A by HIF- prolylhydroxyalses (PHDs) during acute respiratory distress syndrome (ARDS). ARDS is an extreme inflammatory response of the lungs triggered by injury or infection. In surgical patients, ARDS can occur after major surgery and causes dramatic increases in morbidity and mortality. Moreover, ARDS profoundly impacts patients with infections or sepsis, including the recent COVID-19 pandemic. However, only a minor percentage of patients who undergo major surgery or who have lung infections go on to develop ARDS. Therefore, we hypothesized that endogenous adaptive responses exist to protect the lungs from developing severe inflammation causing ARDS. Previous studies from our laboratory identified alveolar-epithelial expressed HIF1A as an endogenous feedback signal controlling excessive alveolar inflammation during ARDS. The current application is focused on examining the "upstream" regulation of HIF1A by PHDs. During hypoxia or ARDS, PHDs are inhibited, thereby promoting the stabilization of HIFs. Three PHD iso-forms are known (PHD1-3). Our preliminary studies indicate that PHD1 is the most abundant PHD in the lungs. Studies using mechanical ventilation to induce ARDS revealed selective repression of Phd1. In addition, pharmacologic inhibition of Phd1 or genetic deletion (Phd1-/- mice) is associated with attenuated lung injury. Moreover, mice with alveolar deletion of Phd1 (Phd1loxp/loxp SPC CreER+) are protected during "conventional" ARDS or infection with the SARS-CoV-2 virus. A screen for miRNAs that mediate PHD1-repression pointed us towards miR-15a/16. Indeed, miR-15a/16 is transcriptionally induced by HIF1A and effectively represses PHD1 during ARDS. In addition, overexpression of miR-16 provides lung protection in conjunction with PHD1 repression and enhanced HIF1A stabilization. Thus, we hypothesize that miR-15a/16-dependent repression of PHD1 and concomitant enhancement of HIF1A stabilization functions in an endogenous feedforward loop critical for attenuating alveolar inflammation during ARDS. We designed four aims to address this hypothesis, including Aim1, which is focused on the interaction of miR15a/16 and PHD1, including proof-of-principle studies in patients with ARDS. In Aim 2, we will pursue in vivo studies in conventional ARDS models. In Aim 3, we are extending our studies towards in vivo models of SARS-CoV-2-associated ARDS using our BSL-3 laboratory at UTHealth. In Aim 4, we will explore therapeutic strategies targeting the miR-15a/16-PHD1 pathway for ARDS treatments. Successful completion of these studies will give us the scientific foundation to move forward with clinical trials targeting individual PHDs or miR-15a/b towards the prevention or treatment of ARDS in surgical patients or patients experiencing pathogen-associated ARDS, such as during COVID-19.

项目总结