AMPK in the Development and Resolution of Lung Fibrosis

AMPK 在肺纤维化的发展和解决中的作用

• 批准号: 10320917
• 负责人: Victor J. Thannickal
• 金额: $ 52.85万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320917
• 关键词: 5' -AMP-activated protein kinase; Affect; Age; Aging; Apoptosis; Asbestos; Asbestos-related lung injury; Autophagocytosis; Basic Science; Bioenergetics; Biogenesis; Biology of Aging; Bleomycin; Chrysotile; Clinical Trials; Collaborations; Complement; Coupled; Cyclic AMP-Dependent Protein Kinases; Development; Diagnosis; Disease; Event; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Functional disorder; Glycolysis; Homeostasis; Impairment; Knock-out; Link; Mediating; Metabolic; Metabolism; Metformin; Mitochondria; Modeling; Mus; Myofibroblast; Natural regeneration; PI3K/AKT; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phenotype; Phospholipase; Phospholipase D; Phosphorylation; Phosphotransferases; Play; Predisposition; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Recovery; Resistance; Resolution; Respiration Disorders; Risk Factors; Role; STK11 gene; Safety; Signal Pathway; Signal Transduction; System; Testing; Therapeutic Intervention; Time; Transgenic Model; Treatment Efficacy; aged; base; body system; efficacy testing; fibrogenesis; fibrotic lung; functional outcomes; genetic approach; idiopathic pulmonary fibrosis; impaired capacity; in vivo; indium-bleomycin; injury and repair; lung injury; mitochondrial dysfunction; mouse model; novel therapeutic intervention; preemptive intervention; preservation; prevent; protein degradation; repaired; response; response to injury; scaffold; sensor; therapeutically effective; translational impact; translational study

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal respiratory disorder affecting ~150,000 patients in US each year. IPF is a disease of aging, with two-thirds of IPF patients over 60 years old at the time of presentation and average age of 66 years at the time of diagnosis. Effective therapeutic interventions are limited. Our proposed studies seek a solution to effectively stop and reverse established fibrosis. This proposal consists of highly mechanistic and translational studies that are result of a collaboration between Dr. Zmijewski and Dr. Thannickal. Both PIs and the collaborators bring complementary expertise in cellular metabolism, myofibroblast biology, aging, and lung injury and repair. We found that AMP-activated protein kinase (AMPK), a key sensor and metabolic regulator, is a viable target in lung fibrosis. In particular, AMPK activity is reduced in IPF lungs and the fibrotic regions following lung injury in mice. Moreover, AMPK inactivation is also associated with age-associated susceptibility to non-resolving fibrosis. This loss of AMPK activity is associated with mitochondrial dysfunction and deficient autophagy/mitophagy, events that are linked to myofibroblast resistance to apoptosis and impaired ECM turnover. We hypothesize that, in the repair response to lung injury, AMPK activation is essential for preservation of mitochondrial homeostasis, autophagy- dependent ECM turnover and myofibroblast sensitivity to apoptosis which promotes resolution of lung fibrosis. Our hypothesis will be tested using three specific AIMs. AIM 1 is focused on AMPK-dependent activation of mitochondrial biogenesis and autophagy/mitophagy to reverse myofibroblast activation and resistance to apoptosis, both in ex vivo cellular systems and in a murine model of lung fibrosis in vivo. AIM 2 will reveal mechanisms responsible for lack of AMPK activation in myofibroblasts, from IPF subjects and from fibrotic lungs of mice. AIM 3 will test the efficacy of AMPK activators on age-associated susceptibility to lung fibrosis. Proof-of-concept studies with pharmacological AMPK activators will include an FDA-approved drug (metformin) and a more specific AMPK activator (AICAR). In addition, genetic approaches will include global AMPK knockouts and fibroblast-specific conditional deletion of AMPK in mice; transgenic models will also incorporate mice deficient for activators of biogenesis and autophagy/mitophagy. If confirmed, our studies will reveal new relationships between lung fibrosis and AMPK dysfunction that affects myofibroblast bioenergetic reprogramming, apoptosis susceptibility, and persistent lung fibrosis. Advancements in the field include signaling mechanisms responsible for AMPK inactivation in IPF and aging. Translational impact be realized by the re- purposing of metformin to treat lung fibrosis. Based on the safety profile of this drug, if the results confirm anti- fibrotic actions of metformin, clinical trials could be proposed to test its efficacy in IPF.

项目摘要 特发性肺纤维化（IPF）是一种进行性且最终致命的呼吸疾病 每年我们〜150,000名患者。 IPF是一种衰老的疾病，有三分之二的IPF患者超过60岁 在诊断时出现时，平均年龄为66岁。有效的治疗 干预措施有限。我们拟议的研究寻求一种解决方案，以有效停止和逆转建立 纤维化。该建议由高度机械和翻译研究组成，这些研究是由协作的 在Zmijewski博士和Thannickal博士之间。 PI和合作者都带来了补充专业知识 细胞代谢，肌纤维细胞生物学，衰老以及肺损伤和修复。我们发现AMP激活 蛋白激酶（AMPK）是一种钥匙传感器和代谢调节剂，是肺纤维化的可行靶标。尤其， 小鼠肺损伤后IPF肺和纤维化区域的AMPK活性降低。而且，AMPK 失活也与年龄相关的非分辨纤维化敏感性有关。 AMPK的损失 活动与线粒体功能障碍和缺乏自噬/线粒体有关的事件有关 对于肌纤维细胞对凋亡的抗性和ECM营业额受损。我们假设这是在维修响应中 要为肺损伤，AMPK激活对于维护线粒体稳态，自噬至关重要。 依赖的ECM周转率和肌纤维细胞对凋亡的敏感性，促进肺的分辨率 纤维化。我们的假设将使用三个特定目标进行检验。 AIM 1专注于依赖AMPK 线粒体生物发生和自噬/线粒体的激活以逆转肌纤维细胞激活和 在离体细胞系统和体内肺纤维化模型中，对凋亡的抗性。目标2 将揭示导致肌纤维细胞，IPF受试者和来自的肌纤维细胞中缺乏AMPK激活的机制 小鼠的纤维化肺。 AIM 3将测试AMPK激活剂对年龄相关肺敏感性的功效 纤维化。药理学AMPK激活剂的概念验证研究将包括FDA批准的药物 （二甲双胍）和更具体的AMPK激活剂（AICAR）。此外，遗传方法将包括全球 AMPK敲除和小鼠AMPK的成纤维细胞特异性删除；转基因模型也将 结合缺乏生物发生激活剂和自噬/线粒体的小鼠。如果得到确认，我们的研究将 揭示肺纤维化和AMPK功能障碍之间影响肌纤维细胞生物能的新关系 重编程，凋亡易感性和持续性肺纤维化。该领域的进步包括信号 导致IPF和衰老中AMPK失活的机制。翻译影响将由重新实现 二甲双胍治疗肺纤维化的目的。基于该药物的安全性，如果结果证实了抗 可以提出二甲双胍的纤维化作用，即可提出临床试验以测试其在IPF中的功效。

项目成果

Autophagy in Idiopathic Pulmonary Fibrosis: Predisposition of the Aging Lung to Fibrosis?

• DOI: 10.1165/rcmb.2022-0379ed
• 发表时间: 2023-01
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4

ZKSCAN3 in severe bacterial lung infection and sepsis-induced immunosuppression.

• DOI: 10.1038/s41374-021-00660-z
• 发表时间: 2021-11
• 期刊: Laboratory investigation; a journal of technical methods and pathology
• 作者: Ouyang X;Becker E Jr;Bone NB;Johnson MS;Craver J;Zong WX;Darley-Usmar VM;Zmijewski JW;Zhang J
• 通讯作者: Zhang J

Myofibroblast Functions in Tissue Repair and Fibrosis: An Introduction.

肌成纤维细胞在组织修复和纤维化中的功能：简介。

• DOI: 10.1007/978-1-0716-1382-5_2
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Thannickal,VictorJ

AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.

• DOI: 10.1038/s41598-021-90573-0
• 发表时间: 2021-06-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bone NB;Becker EJ Jr;Husain M;Jiang S;Zmijewska AA;Park DW;Chacko B;Darley-Usmar V;Grégoire M;Tadie JM;Thannickal VJ;Zmijewski JW
• 通讯作者: Zmijewski JW