Identification of Novel Modulators of Metabolic Efficiency
Abstract
Metabolic syndrome -- a combination of raised blood pressure, increased circulating glucose, and central obesity -- greatly increases the likelihood of an individual developing type 2 diabetes and heart disease. Metabolic syndrome is highly complex and involves a number of factors, such as poor diets, genetic susceptibility, and metabolic and psychosocial stress. In recent years, the number of individuals including military service personnel presenting with features of metabolic syndrome has increased markedly. Therapies that prevent the onset of metabolic syndrome would have significant scientific, medical, and economic impact. However, to date there are no interventions that simultaneously treat these multiple metabolic symptoms or successfully prevent severe disease onset. Mitochondria are subcellular organelles that efficiently produce energy for the cell. When mitochondria function poorly, it has a major negative impact on metabolism and overall health. In fact, dysfunctional mitochondria play a role in the development of many features of metabolic syndrome. Designing drugs that maintain and/or restore the function of mitochondria to treat metabolic syndrome is an innovative strategy with the potential to not only treat, but prevent, disease progression. While the search for drugs that improve mitochondrial function is underway, existing therapies do not show great clinical promise, have limited efficacy, and have severe side effects. Both dietary restriction (DR) -- a reduction in food intake without malnutrition -- and cold ambient temperature stimulate mitochondrial metabolism. These environmental factors offer novel strategies for improving mitochondrial efficiency, but are clinically limited. Alternatively, it is thought that both DR and cold activate unknown factors that improve mitochondrial function. Identification of these factors, which preferentially synthesize mitochondrial proteins, would highlight clinically relevant compounds that elicit the benefits of DR and cold without any negative consequences. In this study, an innovative assay will be developed to identify novel pharmacotherapeutic agents that promote the manufacture and maintenance of efficient mitochondria. These experiments will identify novel compounds, characterize their modes of action, and contribute to a deeper understanding of mitochondrial function and metabolic disease -- the Fiscal Year 2014 Peer Reviewed Medical Research Program Topic Area addressed by this proposal. The discovery and development of a new generation of drugs will help ameliorate and prevent metabolic disease in active duty members, Veterans, their families, and susceptible individuals in the general population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510123
Entities
People
- William Ja
Organizations
- Scripps Research
- United States Army