Simultaneous Expression from both the Sense and Antisense Strand of the Erythropoietin Receptor Gene Mitigates Acute Lung Injury
Abstract
Central Problem: Acute lung injury in combat is a dire condition and a common occurrence in the setting of military combat that can result from a wide variety of insults. Direct lung injury can result from physical trauma to the chest, smoke inhalation that imparts thermal and chemical injuries, and the inhalation of many noxious and toxic compounds delivered as part of chemical warfare. Even in the absence of direct insult to the lungs, injured men and women who suffer trauma to other organs, hemorrhage, shock, infection, or kidney failure, which are all very common in battlefield-related injuries, can develop secondary lung injury (often called adult respiratory distress syndrome or ARDS). ARDS is a serious disease that is often fatal. Currently, the medical profession has no effective way of preventing lung injury other than using face or respiratory masks as barrier protection. The treatment of acute lung injury is largely supportive, awaiting hopefully for spontaneous recovery. A small number of drug treatments have been tried with variable and limited success. Survivors of acute lung injury often suffer chronic disability and breathing difficulties. The field is in desperate need of new therapy. This short study intends to establish a new way of treating this serious condition. Basic Biology: Mechanisms of natural defense by the lung exist, and one strategy is to amplify native defenses to fight acute lung injury. Genes code for proteins. Genes are the blueprints that direct the manufacturing of its corresponding proteins, and the proteins are the actual workers that perform specific biological functions. The erythropoietin receptor (EpoR) gene codes for the EpoR protein. In many organs, the EpoR protein confers protection against noxious insults and promotes tissue repair. Genes are composed of two strands of deoxyribonucleic acid (DNA), which stores heritable information. Most genes are read from only one strand, and the information is translated into the cognate protein. One unusual feature of the EpoR gene is that it is read from both DNA strands, which results in the production of the EpoR protein from one strand, and a second protein called "RopE" from the opposite strand. RopE is capable of repairing DNA. When DNA strands divide, errors can occur that have serious consequences if not recognized and rectified. DNA repair mechanisms correct these errors. While EpoR promotes repair of the cell itself, RopE repairs the genetic material of the cell, namely DNA. When the lung needs to grow or repair itself, EpoR and RopE levels are both increased. It is possible that EpoR and RopE proteins act synergistically to protect the lung during times of injury and repair. This is the hypothesis to be tested and be exploited to enhance the ability of the lung to protect and repair itself. Innovative Approach: One new therapeutic approach to prevent or treat acute lung injury is to simultaneously amplify the levels of both EpoR and RopE, by delivering the corresponding DNA molecules (called complementary DNA or cDNA) to the lung that will increase EpoR and RopE proteins specifically in the lung. One can then test if this maneuver protects the lung from acute injury. One injury model that is easy to induce and produces reliable lung damage is breathing a high concentration of oxygen, a potent toxin. Rodents will undergo oxygen-induced lung injury. EpoR, RopE, or both will be increased in the lung by inhalation delivery of the appropriate cDNA encapsulated inside inert nano-sized particles. The protective effects of EpoR and RopE, individually or in combination, will be evaluated by measuring lung structure, function, and selected markers of tissue damage. Applicability: If this approach works, it will prove, for the first time, a fundamental biologic model of reading from both strands of DNA to generate two proteins that coordinately protect the cell (biologic advance) and provide a new tech
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610113
Entities
People
- Connie Hsia
Organizations
- United States Army
- University of Texas Southwestern Medical Center