Targeting F-box protein 048 in acute lung injury

靶向 F-box 蛋白 048 在急性肺损伤中的作用

• 批准号: 10683699
• 负责人: Toru Nyunoya
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683699
• 关键词: 5' -AMP-activated protein kinase; Acute; Acute Lung Injury; Anti-Inflammatory Agents; Apoptosis; Attenuated; Behavior; Bioenergetics; Biological; C-terminal; CRISPR/Cas technology; Cartoons; Cause of Death; Cells; Cellular biology; Cessation of life; Chemicals; Clinical Trials; Critical Illness; Data; Defect; Disease; Edema; F-Box Proteins; Foundations; Genetic Models; Homeostasis; Hospitals; Human; Immune response; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Invaded; Knockout Mice; Lung; Maintenance; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Muscle; Oxygen; Oxygen Consumption; Pathogenesis; Pathway interactions; Patients; Pattern; Perfusion; Phosphorylation; Phosphotransferases; Play; Pneumonia; Property; Protein Kinase; Proteins; Reactive Oxygen Species; Regulation; Respiratory Diaphragm; Role; Sepsis; Severities; Staphylococcus aureus; System; Testing; Therapeutic; Ubiquitin; Veterans; Work; base; cytokine; design; improved; in silico; in vivo; inhibitor; lung injury; mitochondrial dysfunction; model design; molecular modeling; mortality; novel; novel therapeutics; pathogen; pathogenic microbe; pharmacokinetics and pharmacodynamics; pre-clinical; preservation; protein degradation; response; restoration; sensor; sepsis induced acute lung injury; small molecule; small molecule therapeutics; tissue injury; tissue oxygenation; ubiquitin-protein ligase

Acute lung injury (ALI) is a devastating disorder among Veterans commonly occurring after sepsis or severe pneumonia. Two key manifestations of ALI are a fundamental inability to extract oxygen and inflammation, both of which may have a mitochondrial basis. Although ALI subjects have mitochondrial defects, the molecular mechanisms underlying their injury that disrupt oxygen consumption and trigger inflammation remain unclear. The mechanistic basis of this proposal resides on our discovery of a unique molecular model of mitochondrial injury whereby a new protein, Fbxo48, potently disrupts mitochondrial function to trigger inflammation by mediating degradation of a crucial cytoprotective, anti-inflammatory energy sensor, 5′-AMP-activated protein kinase (AMPK). By targeting the C-terminal molecular signature present in Fbxo48, we designed, synthesized, and tested a novel small molecule, BC-1618, that stabilizes AMPK levels, preserves mitochondrial function, and reduces inflammation in murine and human ALI models. Thus, in this application we will first elucidate how a common pathogen, S. aureus, depletes AMPK through Fbxo48, thereby accentuating experimental ALI (Aim 1). We will specifically elucidate how Fbxo48 targets AMPK for its degradation using complementary in vitro and in vivo genetic models, including CRISPR/Cas9 Fbxo48 knockout mice. Next we will examine the pharmacokinetic and pharmacodynamics properties of BC-1618 focusing on its mitochondrial-protective and anti- inflammatory properties in ALI models (Aim 2). A unique approach in this application is execution of small molecule testing in an ex vivo human lung perfusion system. These studies will provide a new pathobiologic model of mitochondrial injury that will serve as a platform for presenting the first-in-class dual acting small molecule modulator that optimizes cellular bioenergetics and limits inflammation in subjects with severe critical illness.

在 败血症或严重的肺炎。阿里的两种关键表现是基本的无力 提取氧气和注射，两者都可能具有线粒体基础。虽然 ALI受试者具有线粒体缺陷，其损伤的分子机制 这种破坏氧气消耗和触发剂仍不清楚。机械 该提议住宅的基础是我们发现线粒体的独特分子模型 损伤，新蛋白FBXO48可能会破坏线粒体功能以触发 通过介导关键的细胞保护，抗炎能的降解来炎症 传感器，5'-AMP激活的蛋白激酶（AMPK）。通过靶向C末端分子 我们在FBXO48中存在的签名，我们设计，合成并测试了一个新型的小分子， BC-1618，稳定AMPK水平，保持线粒体功能并降低 鼠和人类Ali模型中的炎症。在此应用程序中，我们将首先阐明 普通病原体，金黄色葡萄球菌如何通过FBXO48耗尽AMPK，从而突出 实验ALI（AIM 1）。我们将专门阐明FBXO48如何将AMPK靶向AMPK 使用完整的体外和体内遗传模型降解，包括 CRISPR/CAS9 FBXO48淘汰小鼠。接下来，我们将检查药代动力学和 BC-1618的药效学特性，重点是其线粒体保护和抗 ALI模型中的炎症特性（AIM 2）。该应用程序中的一种独特方法是 在体内人肺灌注系统中执行小分子测试。这些 研究将为线粒体损伤提供新的病理生物学模型，该模型将作为一个 呈现优化的第一类双重表现小分子调节器的平台 细胞生物能学和限制严重危重疾病的受试者的炎症。

项目成果

Synthesis and Characterization of a Resin/Acrylamide-2-acrylamide-2-methylpropane Sulfonate-Diallyl Dimethyl Ammonium Chloride-N-vinyl-2-pyrrolidinone Polymer Microcapsule Gelling Agent for Oil and Gas Field Transformation.

• DOI: 10.1021/acsomega.3c06989
• 发表时间: 2023-12-26
• 期刊: ACS OMEGA
• 影响因子: 4.1
• 作者: Liu, Yunfeng;Zhou, Lang;Tang, Yongfan;Liu, Qiang;Li, Wei;Zhang, Yan
• 通讯作者: Zhang, Yan

Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis.

顺铂和 Chal-24 组合通过 IAP 和 c-FLIPL 降解、核糖体形成和自噬介导的细胞凋亡发挥协同抗癌作用。

• DOI: 10.18632/oncotarget.2746
• 发表时间: 2015-01-30
• 期刊: Oncotarget
• 作者: Shi S;Wang Q;Xu J;Jang JH;Padilla MT;Nyunoya T;Xing C;Zhang L;Lin Y
• 通讯作者: Lin Y

ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis.

• DOI: 10.1111/acel.12720
• 发表时间: 2018-04
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Bueno M;Brands J;Voltz L;Fiedler K;Mays B;St Croix C;Sembrat J;Mallampalli RK;Rojas M;Mora AL
• 通讯作者: Mora AL