A novel protective mechanism in hemorrhagic shock

失血性休克的新型保护机制

• 批准号: 10434853
• 负责人: TING C ZHao
• 金额: $ 33.62万
• 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/10434853
• 关键词: Ablation; Attenuated; Binding; Biological Assay; CRISPR/Cas technology; Cause of Death; Cells; ChIP-seq; 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.

出血性休克是美国和全球死亡和残疾的主要原因。的患者 在最初的出血和创伤损伤中存活的患者功能结局较差， 长期死亡率。快速控制出血的管理对于提高患者的生存率至关重要。 手术中休克的病人值得注意的是，全身性胰岛素抵抗和代谢紊乱表现为 创伤和出血中最常见的病理过程。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 控制出血和创伤中代谢紊乱的策略已被公认为是 最有前途的手术疗法骨骼肌是重要的分泌器官， 许多肌因子，在对抗胰岛素抵抗和代谢紊乱方面具有关键作用。Irisin，a 一种新发现的激素，从纤连蛋白III型结构域5（FNDC 5）裂解，是限制性分泌的 从骨骼肌中提取胰岛素来调节胰岛素敏感性。值得注意的是，鸢尾素受体整合素IRRIV 5（IRRIV） 最近被鉴定为与鸢尾素偶联以引发信号通路。我们激动人心的发现 Irisin在通过AMPK途径改善骨骼肌细胞胰岛素敏感性中具有关键作用。我们发现 出血导致骨骼肌中鸢尾素和鸢尾素受体的显著减少。而且有 Irisin可显著减轻出血时全身胰岛素抵抗的严重损害。引人注目的是， 使用CRISPR/Cas9基因组编辑技术在体内缺失鸢尾素诱导了严重的胰岛素抵抗， 在整个身体。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，以及细胞因子的大规模测定， 我们将检验我们的中心假设，即鸢尾素与鸢尾素受体偶联对调节胰岛素起关键作用， 在遗传、细胞和全身水平上抵抗出血。将开展拟定研究 基于这三个具体目标。具体目标#1：确定鸢尾素/鸢尾素受体IRRIV调节及其作用 对线粒体功能的影响。具体目标#2：确定 鸢尾素及其受体在调节胰岛素抵抗和代谢紊乱中的作用 出血具体目标#3：确定鸢尾素和鸢尾素受体IRRIV是否介导衰老诱导的 心脏抑制、炎性细胞因子和超微结构损伤。总体而言，拟议的研究 将首次定义鸢尾素/鸢尾素受体在介导胰岛素抵抗中的关键功能， 出血时的代谢紊乱。该提案揭示了理解这种机制的新见解。 在现场大出血更重要的是，对Irisin/Irisin受体的功能作用的研究具有希望 在出血和手术治疗方面开发一种全新的疗法。