1. "Mitochondrial Ca²⁺ Transport in Heart Cells," NIH HL 33333

Our immediate efforts are to characterize the mitochondrial Ca²⁺ influx and efflux mechanisms in cardiac muscle cells and determine how these mechanisms regulate excitation-contraction coupling. Our working hypothesis is that cardiac mitochondria contain a Ca²⁺-activated, ryanodine-sensitive and a Ca²⁺-activated cyclosporin-sensitive Ca²⁺ permeable channel that are responsible for the fast uptake of Ca²⁺ into and fast release of Ca²⁺ out of mitochondria, respectively. These dynamic Ca²⁺ transport systems participate actively in regulating cardiac excitation-contraction coupling process, due to their structural proximity to the junctions between sarcoplasmic reticulum and L-type Ca²⁺ channels.


2. "Mitochondrial Ca²⁺ Transport in Hypertrophied and Failing Heart," AHA 0050839T

Our main objective is to determine the role of mitochondrial Ca²⁺ transport underlying cardiac hypertrophy and heart failure. The working hypothesis is that a reduction in the magnitude of Ca²⁺ sequestration by mitochondria, either due to a displacement of mitochondria from Ca²⁺ release sites of sarcoplasmic reticulum and L-type Ca²⁺ channels and/or a defect in mitochondrial Ca²⁺ uptake mechanisms, leads to a reduction in cardiac contractility and ATP production (heart failure).


3. "Mitochondrial Modulation of Neuronal Excitotoxicity," NIH NS 37710

Our immediate goal is to determine the role of mitochodrial Ca²⁺ overload and oxidative stress in neuronal cell death. Our working hypothesis is that Ca²⁺- and ROS-dependent mitochondrial permeability transition (MPT) opening is central to the process of excitotoxic cell death, and that energetically impaired cells are more susceptible to excitotoxic cell death because they have a higher likelihood of MPT occurrence in response to a given excitotoxic stimulus.


4. "Mitochondrial Glutathione: Protection Against Spinal Cord Injury," New York State Research CO17688

In this proposal, we will test the hypothesis: "Enhancement of mitochondrial glutathione concentration ameliorates oxidative stress-induced damage to spinal cord neurons." The information obtained from the present investigation will not only test a unique hypothesis of how reactive oxygen species (ROS) mediates spinal cord injury (SCI) but will also provide new and novel strategies for the development of therapeutic agents for the treatment of SCI.

This research will provide important information regarding the fundamental principles of mitochondrial Ca²⁺ transport mechanisms in heart and neuronal cells. This information is critical for our understanding of the participation of mitochondria in the etiology of cardiovascular diseases such as cardiac arrhythmia, cardiomyopathy, and heart failure as well as neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and spinal cord injury. Ultimately, it will provide insights to design novel targets for therapeutic intervention in these diseases.