Objectives: The objective of this equipment request is to obtain a state-of-the-art instrument to measure mitochondrial function in order to serve the research needs of investigators at the VA Portland Health Care System facility (VAPORHCS). In fiscal year 2018, VAPORHCS scientists were successful in competing for over $32 million in research grants from the VA, NIH, DOD and other sources. The VAPORHCS ranks 7th among all VAs nationwide in total research funding. There are 10 career development award or K-award recipients currently being trained here. Research is conducted in a total of 96,000 square feet of wet and dry lab space that supports programs in basic science, clinical research, rehabilitation, health services, cooperative studies, epidemiology and outcomes research. VAPORHCS is home to Centers of Excellence funded by the VA in Auditory Research and Health Services Research, and an NIH- funded Alcohol Research Center. Clinical programs awarded to the VAPORHCS include a NODES, NAVIGATE, MVP recruiting site, MIRECC, PADRECC, Centers for Multiple Sclerosis and Epilepsy, and Centers funded by QUERI and AHRQ. Plan: The plan is to obtain a Seahorse analyzer and locate it in the Portland VA facility to serve as a shared resource for VA investigators whose research involves measurement of mitochondrial respiration. Planned studies by the six VA-funded investigators include: measurement of mitochondrial respiration for: 1) the evaluation of candidate therapies in cell culture and animal models of Alzheimer?s disease, 2) evaluation of antimalarial drugs, 3) evaluation of drugs for the treatment of toxoplasmosis, 4) evaluation of the functional significance of succinate dehydrogenase mutations in stromal cell cancer cells, 5) evaluation of candidate therapies in a toxin model of Parkinson?s disease, and 6) evaluation of the effects of traumatic brain injury upon brain cell mitochondria. Once the instrument is in place, additional investigators are expected to take advantage of it. Methods: The tissue source for the measurements will vary across the respective laboratories, with mitochondrial respiration measured in cultured cells, in parasites, and in mitochondria isolated from brain tissue, depending on the research program. The Seahorse analyzer measures basal and maximum mitochondrial energy consumption and a number of other metrics are calculated from these values. Clinical relevance: The investigators participating in this request perform research which is intended to be translated to clinical application, and several have advanced their preclinical work to clinical trials, including treatments for Alzheimer?s disease, cancer, malaria, toxoplasmosis, and traumatic brain injury. The research supported by this instrument consequently has a high likelihood of leading to interventions to improve the health of veterans. Relevance to the VA?s mission: The treatment of neurodegenerative disease, cancer, infectious disease, and traumatic brain injury are all important for the VA?s mission. Two of the conditions under study are especially relevant to the VA: Parkinson?s disease is a service- connected illness for veterans with a history of exposure to Agent Orange exposure and traumatic brain injury is the signature injury for veterans of recent conflicts in Iraq and Afghanistan.
Measurement of the function of mitochondria, the organelles which produce energy in all types of cells, is valuable to scientists from diverse fields, from neuroscience to infectious disease to oncology. The development of the Seahorse instrument has made accurate and precise measurements of mitochondrial oxygen consumption available with an efficient, user-friendly technology. The seven investigators on this application are poised to take advantage of this technology in their current research, and other investigators are expected to become interested as the availability and the scientific power of this methodology becomes more widely known. The planned use of this instrument is expected to lead to improvements in veterans? health, based on the track record of the participating investigators in translating their research to the clinic.
