A novel protective mechanism in hemorrhagic shock

失血性休克的新型保护机制

• 批准号: 10185587
• 负责人: TING C ZHao
• 金额: $ 41.15万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185587
• 关键词: Ablation; Attenuated; Binding; Biological Assay; CRISPR/Cas technology; Cause of Death; Cells; ChIP-seq; Cleaved cell; Coupling; Deacetylation; Failure; Fibronectins; Functional disorder; Genetic; HDAC4 gene; Hemorrhage; Hemorrhagic Shock; Hormones; Impairment; Inflammatory; Insulin Receptor; Insulin Resistance; Integrins; Intervention; Investigation; Knock-out; Knockout Mice; Ligands; Maintenance; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Mitochondria; Multiple Organ Failure; Muscle; Operative Surgical Procedures; Organ; Pathologic Processes; Pathway interactions; Patients; Physiological; Play; Resources; Risk; Role; Severities; Shock; Signal Pathway; Skeletal Muscle; System; Techniques; Technology; Testing; Time; Trauma; United States; adverse outcome; attenuation; base; cardiac depression; cytokine; disability; functional outcomes; genome editing; improved; in vivo; insight; insulin sensitivity; insulin signaling; knock-down; mortality; mouse model; nanoGold; nanoparticle delivery; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; receptor; response; skeletal; spatiotemporal

Hemorrhagic shock in a major cause of death and disability both in the United State and globally. Patients who survive the initial hemorrhage and trauma insult have poor functional outcomes and significantly increased long term mortality. The management of rapid hemorrhage control is critical for improving survival in shocked patient in surgery. Notably, systemic insulin resistance and metabolic disorders manifested as one of the most common pathological processes in trauma and hemorrhage. The intervention for suppressing insulin resistance and metabolic stress remarkably reduced the mortality of trauma and hemorrhage patients. Thus, the strategy for controlling metabolic disturbances in hemorrhage and trauma has been recognized as one of the most promising therapies in surgery. Skeletal muscle serves as an important secretory organ that secrete numerous myokines, which have crucial roles in countering insulin resistance and metabolic disorders. Irisin, a newly identified hormone, cleaved from Fibronectin type III domain containing 5 (FNDC5), is restrictedly secreted from the skeletal muscle resource to regulate insulin sensitivity. Notably, the irisin receptor integrin V5 (IRRIV) was recently identified to couple with irisin for eliciting a signaling pathway. Our exciting discovery has identified irisin as having a key role in improving insulin sensitivity in skeletal cells via AMPK pathway. We have found that hemorrhage resulted in a marked decrease in irisin and irisin receptor in skeletal muscle. Furthermore, a profound impairment in systemic insulin resistance in hemorrhage was remarkably mitigated by irisin. Strikingly, the deletion of irisin using CRISPR/Cas9 genome editing technology in vivo induced a profound insulin resistance in the whole body. By using newly developed CRISPR/Cas9 genome editing technology, non-viral Gold- nanoparticle delivery system, high throughput next generation sequencing, and large-scale assay of cytokines, we will test our central hypothesis that irisin coupling with irisin receptor contributes critically to modulating insulin resistance in hemorrhage at the genetic, cellular, and whole body levels. The proposed studies will be performed based on the three specific aims. Specific Aim #1: Determine irisin/irisin receptor IRRIV modulation and their impact on mitochondrial function in response to hemorrhage and trauma. Specific Aim #2: Determine the functional role of irisin and irisin receptor in modulating systemic insulin resistance and metabolic disorder in hemorrhage. Specific Aim #3: Determine whether irisin and irisin receptor IRRIV mediate hemorrhage-induced cardiac depression, inflammatory cytokines and ultrastructural damage. Taken together, the proposed studies will for the first time define the crucial function of the irisin/irisin receptor in mediating insulin resistance and metabolic disorders in hemorrhage. The proposal uncovers novel insight into understanding the mechanism of hemorrhage in the field. More importantly, investigation of the functional role of irisin/irisin receptor holds promise in developing an entirely new therapy in hemorrhage and surgical therapy.

失血性休克是美国和全球死亡和残疾的主要原因。患者 在最初的出血和创伤中存活下来的侮辱有较差的功能结局，并显著延长了时间 足月死亡率。快速控制出血的管理是提高存活率的关键 手术中病人休克。值得注意的是，全身性胰岛素抵抗和代谢紊乱表现为 创伤和出血最常见的病理过程。抑制胰岛素的干预 抵抗力和代谢应激显著降低创伤和出血患者的死亡率。因此， 控制出血和创伤时代谢紊乱的策略已被公认为 手术中最有希望的疗法。骨骼肌是一种重要的分泌器官，可以分泌 大量的肌动蛋白，它们在对抗胰岛素抵抗和代谢紊乱方面起着关键作用。淫羊藿素，一种 新发现的激素是从含有5(FNDC5)的纤维连接蛋白III型结构域中切割出来的，是限制性分泌的 从骨骼肌资源中调节胰岛素敏感性。值得注意的是，虹膜受体整合素V5(IRRIV) 最近被发现与淫羊藿素偶联，以诱导一条信号通路。我们令人兴奋的发现确定了 淫羊藿素通过AMPK途径在提高骨骼细胞的胰岛素敏感性中起关键作用。我们发现， 失血后骨骼肌中虹膜蛋白及其受体明显减少。此外，a 血管紧张素可显著减轻出血患者胰岛素抵抗的严重损害。令人惊讶的是， 利用CRISPR/Cas9基因组编辑技术体内缺失淫羊藿素可导致严重的胰岛素抵抗 全身都是。通过使用新开发的CRISPR/Cas9基因组编辑技术，非病毒Gold- 纳米颗粒递送系统、高通量下一代测序和大规模细胞因子检测， 我们将验证我们的中心假设，即虹膜蛋白与虹膜蛋白受体的偶联在调节胰岛素中起关键作用。 在遗传、细胞和全身水平上对出血的抵抗。将进行拟议的研究 基于这三个具体目标。特定目标#1：确定虹膜蛋白/虹膜蛋白受体IRRIV的调节及其 出血和创伤对线粒体功能的影响。具体目标2：确定 淫羊藿素及其受体在调节全身胰岛素抵抗和代谢紊乱中的作用 大出血。具体目标#3：确定虹膜蛋白及其受体IRRIV是否介导失血 心脏抑制、炎性细胞因子和超微结构损伤。总而言之，拟议的研究 将首次确定虹膜蛋白/虹膜蛋白受体在介导胰岛素抵抗和 出血时的代谢紊乱。该提案揭示了对理解疾病机制的新见解。 田野里的出血。更重要的是，研究虹膜蛋白/虹膜蛋白受体的功能作用是有希望的。 开发了一种全新的出血和外科治疗方法。