A novel protective mechanism in hemorrhagic shock

失血性休克是美国乃至全球死亡和残疾的主要原因之一。病人

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.