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.

项目概要 特发性肺纤维化（IPF）是一种进行性且最终致命的呼吸系统疾病，影响 美国每年约有 150,000 名患者。 IPF是一种衰老性疾病，三分之二的IPF患者年龄超过60岁 就诊时的平均年龄为 66 岁。有效治疗 干预措施有限。我们提出的研究寻求一种解决方案，以有效阻止和逆转已建立的 纤维化。该提案包括高度机械化和转化性研究，这些研究是合作的结果 Zmijewski 博士和 Thannickal 博士之间。 PI 和合作者都带来了互补的专业知识 细胞代谢、肌成纤维细胞生物学、衰老以及肺损伤和修复。我们发现 AMP 激活 蛋白激酶 (AMPK) 是一种关键的传感器和代谢调节剂，是肺纤维化的可行靶点。尤其， 小鼠肺损伤后，IPF 肺部和纤维化区域的 AMPK 活性降低。此外，AMPK 失活还与年龄相关的非消退性纤维化易感性有关。 AMPK 的缺失 活性与线粒体功能障碍和自噬/线粒体自噬缺陷有关，这些事件与 肌成纤维细胞对细胞凋亡的抵抗力和 ECM 更新受损。我们假设，在修复反应中 对于肺损伤，AMPK 激活对于维持线粒体稳态、自噬至关重要 依赖 ECM 周转和肌成纤维细胞对细胞凋亡的敏感性，促进肺的消退 纤维化。我们的假设将使用三个特定的目标进行测试。 AIM 1 专注于 AMPK 依赖 激活线粒体生物发生和自噬/线粒体自噬以逆转肌成纤维细胞激活和 在离体细胞系统和体内肺纤维化小鼠模型中均具有对细胞凋亡的抵抗力。目标2 将揭示导致 IPF 受试者和肌成纤维细胞中 AMPK 激活缺乏的机制 小鼠肺纤维化。 AIM 3 将测试 AMPK 激活剂对与年龄相关的肺部易感性的功效 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 小鼠中 AMPK 敲除和成纤维细胞特异性条件性 AMPK 缺失；转基因模型也将 纳入缺乏生物发生和自噬/线粒体自噬激活剂的小鼠。如果得到证实，我们的研究将 揭示肺纤维化与影响肌成纤维细胞生物能的 AMPK 功能障碍之间的新关系 重编程、细胞凋亡易感性和持续性肺纤维化。该领域的进步包括信号传输 负责 IPF 和衰老中 AMPK 失活的机制。转化影响可以通过重新实现 二甲双胍治疗肺纤维化的目的。根据该药物的安全性，如果结果证实抗 由于二甲双胍的纤维化作用，可以进行临床试验来测试其对 IPF 的疗效。

项目成果

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

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

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