Research in the Antonio De Maio Laboratory

Genetic and Molecular Mechanisms of the Response to Stress

Trauma is the third leading cause of death in the United States.  Frequency of mortality after trauma is complicated by the patient’s response to injury.  For example, the initial insult could trigger a situation of exaggerated inflammatory response that results in organ dysfunction and death. The response to injury is modulated by several components, including the injury itself, the environment, sex, age, and genetic make-up of the patient (see Figure).  The objective of our laboratory is to understand the response to injury at the genetic and molecular levels.  The genetic component of the response to injury (inflammation) is studied using inbred mouse strains (see Figure).Key genes that are involved in the regulation of the inflammatory response are mapped using classical mouse genetic methods (see Figure). These genes can be used as genetic markers to identify a particular susceptibility to disease in humans. In addition, the molecular pathways in which these genes are involved can be investigated in isolated cell populations, such as macrophages.

Another important component of the response to injury is the expression of genes encoding heat shock or stress proteins (see Figure). These proteins have a major function as molecular chaperones. In addition, the presence of these proteins confers protection to cells from subsequent stresses, a phenomenon coined stress tolerance. Early studies from our laboratory have shown that Hsp70, the major inducible form of heat shock protein family, could interact with membranes forming ion conductance pathways (see Figure) and regulating vesicle trafficking. Recently, we found that Hsp70 could be detected inserted in the plasma membrane of stressed cells (see Figure), and it is released into the extracellular environment in a membrane-associated form. These membranes containing Hsp70 can activate macrophages with great specificity and potency. We speculate that membrane-bound extracellular Hsp70 is a major regulator of the immune system. Our laboratory is currently investigating the mechanism of Hsp70 insertion into membranes, export and interaction with cells of the immune system.

The information generated from these studies may eventually help in the care of critically ill patients.