Grant: Operating Grant

When bacteria or viruses enter the bloodstream, the body has to recognize these foreign infectious agents and then respond to contain these agents. Infectious agents are recognized by a family of proteins on the cell surface called Toll-like receptors (TLR). When TLRs recognize the presence of an infection they send a signal to the inside of the cell called an innate immune signal. Innate immune signals immediately begin a process called inflammation. Inflammation is the response of the body to contain infectious agents by bringing white blood cells (infection-fighting cells) to the site of the infection. However, depending on the type of infection and/or the response of the person getting the infection sometimes the process of inflammation functions incorrectly which causes various organs in the body to fail. This response of the body that occurs when various organs function poorly during severe infections is called septic shock. Septic shock occurs because the body responds inappropriately to chemicals that make up bacteria and viruses, which then impair the normal process of inflammation. Despite the continuing development of new antibiotics, when specific bacteria enter the blood and cause septic shock, the death rate is very high. It is thought that alteration of blood vessel stability plays a crucial role in this process. This proposal is designed to understand how the cells lining the inside of blood vessels, called endothelial cells, respond to bacterial and viral components through TLR. We are interested in the molecular signals within the endothelial cell that regulate the responses to infections. We have discovered a new gene that we believe plays a role in regulating the signal transmitted by specific TLRs. The studies in this grant are designed to understand how this molecule functions to send signals within the endothelial cell, and to determine whether blocking this signal can alter the outcome during septic shock.