Grant: Discovery Grants Program - Individual

The mammalian immune system has evolved the ability to efficiently respond and protect its hosts from potentially harmful and lethal pathogens. While this inflammatory process is often very effective, it is critical that our immune system can sense when there is no longer a threat/immune challenge and is able to return to a resting, yet still vigilant state. This important balance is achieved by the immense plasticity and ability of immune cells to transition between effector and regulatory states. It is widely accepted that cells of both the innate (e.g. macrophages) and adaptive (e.g. T B cells) immune systems can perform a variety of functions, including those directly related to promoting and resolving inflammation. A functional immune system requires a tightly regulated balance of communication signals between cells of both the innate and adaptive immune systems. Immune cells are continually receiving input from their local microenvironment via both soluble and membrane-bound molecules that influences whether they remain quiescent (i.e. resting) or become activated. Upon activation, immune cells dramatically change their metabolism to compensate for the increase in energy demands. Only until recently have we now begun to appreciate the importance of metabolism and mitochondrial function in its capacity to participate in immune cell function. In immune cells, mitochondria do not only function as a bioenergetic organelle, but also plays a significant role during cell proliferation, survival, and differentiation. Under normal and resting conditions, immune cells are required to generate sufficient levels of ATP (the body's fuel) to maintain proper function. However, upon activation, immune cells responding to danger signals or foreign pathogens can quickly change their cellular metabolism to a form that is less reliant on mitochondrial-generated ATP (i.e. glycolysis). The molecular mechanisms and the significance/impact of these changes in immune cell metabolism are unclear. MicroRNAs are a family of short non-coding RNA molecules that regulate the production of proteins in mammals. It is estimated that microRNAs are responsible for regulating up to 70% of the genes that are expressed in humans. In many disease states, microRNA levels are dysregulated, however, the significance of these microRNA changes and their effects on mitochondrial function and cellular metabolism have not been investigated. The objectives of this research program are extremely novel and will assess the roles of microRNAs in contributing to overall mitochondrial function and cellular bioenergetics in cells of the human immune system. It is expected that the results of these studies will help further understand the role of the mitochondria in immune cells and the involvement of microRNAs that have been previously implicated in human health and disease.