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How can molecules in the lining of blood vessels impact brain health after an individual has an infection?
Alejandro Adam, Ph.D.
Albany Medical College
Albany, NY - United States
Background
Sepsis (infection of the blood) occurs when the bloodstream is overwhelmed by bacteria, viruses, or parasites. When sepsis takes place, the body releases a large number of cytokines (proteins that signal immune cells to attack the invading substances), which can cause the immune system to become overactive and target the body’s organs. This “cytokine storm” may result in the organs beginning to shut down and risking the life of the person with sepsis. In addition, research indicates that individuals with sepsis have a high risk for developing “post-shock” damage to the brain’s structure and function – damage that can lead to memory loss and dementia. However, the exact links between sepsis and dementia risk remain unclear.
More recent studies indicate that molecular processes in the endothelium (a thin layer of cells that cover the inside of blood vessels) may play a role in post-shock brain impairments. According to this research, an endothelial cytokine called interleukin-6 (IL-6) contributes to the immune response to sepsis by activating another protein in endothelial cells called STAT3 (signal transducer and activator of transcription 3). For individuals with high levels of cytokine IL-6, this STAT3-related immune response may become harmful and lead to brain damage. Other studies have found that a third endothelial protein called SOCS3 (suppressor of cytokine signaling 3), which limits the activities of cytokines, may help prevent IL-6 from creating an overactive immune response. Taken together, these findings suggest a protective role for SOCS3 in maintaining brain health after septic shock.
Research Plan
Dr. Alejandro Adam and colleagues will study endothelial proteins and post-septic brain damage utilizing genetically-engineered mice which lack either STAT3 or SOCS3. First, the mice will undergo septic-like shock. The researchers will then administer tests of memory to the mice and examine their brains for changes linked to dementia (such as inflammation and brain blood vessel damage). They will then determine if the mice lacking SOCS3 experienced less cognitive loss and brain damage than the mice lacking STAT3. Then, Dr. Adam and team will analyze the endothelial translatome (all the newly formed proteins in the endothelium) in another group of mice with or without SOCS3 that have undergone septic-like shock. This will identify specific genetic changes that help determine how SOCS3 may limit sepsis-related brain blood vessel damage and brain inflammation.
Impact
Results from this project could refine our understanding of how the endothelium impacts brain structure and function after a traumatic event. They could also point to novel therapies for post-shock disorders that target endothelial mechanisms.
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