Research Project: Innate Immune Signaling and Type I Interferon Responses as Novel Modifiers of Mitochondrial Disease Pathology
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- West, Laura
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Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Area: Mitochondrial Disease
Mitochondrial diseases are a group of disorders caused by the malfunction of cellular organelles called mitochondria. Because mitochondria are responsible for generating the energy that powers vital cellular processes, mitochondrial malfunction can result in extensive disease throughout the body, including the nervous, musculoskeletal, digestive, and reproductive systems. Much of the research on mitochondrial disease has focused on the role of mitochondria in energy generation. However, recent studies have shown that mitochondria are key regulators of the immune system and orchestrate many aspects of inflammation during viral or bacterial illness, as well as in non-infectious diseases. In fact, abnormal inflammatory responses have been implicated in a number of diverse pathologies, some of which are present in the multi-organ disease of patients afflicted with mitochondrial syndromes. It is therefore possible that mitochondrial dysfunction aberrantly engages the immune system, resulting in inflammatory responses that exacerbate the pathology of mitochondrial disorders.
To test this hypothesis, we will use a mouse model of mitochondrial disease (called POLG-mutator mice) that mirrors pathology seen in human patients with mitochondrial disease. We will use an array of techniques to characterize inflammatory responses through the progression of disease in these mice. Next, we will use POLG-mutator mice deficient in key immune signaling pathways to determine whether the absence of these pathways attenuates mitochondrial dysfunction and disease, thus demonstrating their importance in driving it. Based on preliminary studies, we predict that inhibition of the immune system will slow or alleviate pathology in this mouse model of mitochondrial disease.
This proposal is innovative in several ways. First, it will examine the novel, unexplored paradigm that inflammatory mechanisms exacerbate multi-organ pathology in mitochondrial disorders and will provide a robust foundation for future research that focuses on immune pathology of mitochondrial diseases in other experimental and clinical settings. Second, there are presently no cures for many mitochondrial disorders, and few treatments are available to slow the progression of these diseases. This research may lay the foundation for studies exploring the therapeutic targeting of inflammatory pathways as a means to attenuate multi-system pathology of mitochondrial diseases.
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