Here we propose a center for collaborative studies that exploits transformational in vivo diagnostic tools to reveal the roles of mitochondria and cell energetics in cell health and disease using mouse and human muscle model systems. Mitochondria are now widely recognized as a nexus between cell energetics, oxidative stress, and cell survival in age-related degenerative diseases, cancer, heart disease and diabetes. An explosion of genetic models of mitochondrial dysfunction and human disease models provides an extraordinary opportunity for innovative new tools to reveal mitochondria's role in specific disease pathologies, especially in human tissues. Transformational tools that provide a new window on the cell to fully exploit these model systems are the core of the proposed center. The proposed initiative will fill the void in non-invasive approaches to study mitochondria in vivo to reveal how they ensure cell health but fail in symptomatic disease. Innovative magnetic resonance (MRS) and optical spectroscopic (OS) approaches permit measuring - for the first time in vivo - three key classes of energetic properties impacted by pathology: mitochondrial coupling (ATP/O2 or P/O) and capacity (O2max), cell glycolysis and ATP level, and cellular and vascular oxygenation (PO2). The proposed Translational Center will provide these tools and innovative approach for collaborative studies;provide new infrastructure for high throughput analyses, and new technical developments for improved measurements.
Aim #1 establishes the Translational Center. Three steps are involved: 1) new personnel are hired and trained in the innovative tools and approaches, 2) new infrastructure is established to permit collaborative studies both locally and nationally and 3) new procedures and protocols are established to standardize the approach between mouse and human models for translational comparisons.
Aim #2 integrates the spectroscopic tools for high throughput studies. OS and MRS probes are engineered to permit parallel spectroscopic measurements for increased throughput and expanded application for both mouse and human studies. New optical technical developments will greatly increase sensitivity and expand the subject populations available for our studies.
Aim #3 disseminates these in vivo diagnostic methods to other sites involved in aging research. We propose to extend our success in dissemination to establish our in vivo diagnostic approach at 3 new research sites with high field clinical magnets and ongoing studies of aging human muscle. This will expand opportunities for critical breakthroughs as diverse research groups apply our innovative methods to a wide array of new experimental programs. The clinical relevance of the proposed center is the development of an approach that will transform our understanding of the role of mitochondrial dysfunction in disease by providing 1) new tools for disease diagnosis, 2) new insights into disease mechanisms, and 3) a new capability for monitoring interventions to halt or reverse disease symptoms. It will also promote economic stimulus through the hiring and retention of 5 new long-term positions and the purchase of 3 major pieces of equipment.
This work is relevant to human health because mitochondrial dysfunction is involved in most degenerative diseases, including diabetes, Parkinson's disease, Huntington's disease, and normal aging. However, there is a gap in our understanding of the role of mitochondrial dysfunction in these diseases due to a gap in our tools study mitochondrial function in vivo. We propose to create a new Translational Center for In Vivo Mitochondrial Medicine to further develop and expand our unique tools for in vivo study of mitochondrial function and cell energetics. This new initiative will facilitate new insights into the conditions that determine whether energetic stress leads to cell adaptation, as in healthy tissue, or cell loss and degeneration, as in diseases states. The goal of this new center will be to make our in vivo approach accessible to the broader research community to accelerate critical breakthroughs and translate these breakthroughs into clinical applications. The requested funds will be used to hire and train at least five new long-term positions and expand the infrastructure to increase the throughput of our experiments and analyses.
Showing the most recent 10 out of 18 publications
