Project Summary/Abstract
Heart failure is the leading cause of death in the United States and represents a major burden on the US
healthcare system. Mitochondrial dysfunction and disruption of cellular energetics are heavily implicated in the
pathogenesis of heart disease. A key regulator of mitochondrial function is Ca2+ uptake through the mitochondrial
calcium uniporter complex (“the uniporter”). The uniporter regulates cytosolic Ca2+ transients, oxidative
phosphorylation, and cell death pathways. However, the molecular mechanisms that control uniporter activation
are not well resolved. Further insight into how the uniporter is regulated would increase our understanding of
mitochondrial Ca2+ signaling and inform the development of therapeutics aimed at modulating uniporter activity.
The Research Training Plan involves using a multidisciplinary approach to investigate how key signaling
molecules and regulatory factors control uniporter activity. Understanding the molecular mechanisms of the Ca2+-
dependent regulation of the uniporter and elucidating a novel gating mechanism will produce a major advance
in the field. The PI will receive comprehensive training to carry out structural, biophysical, biochemical, and
functional studies on membrane transport proteins. The Career Development Plan is tailored to help the PI
develop skills in experimental approaches, research design, project management, mentorship, and written and
oral communication. The sponsor, together with the environment, offers strong support for the PI’s training and
career development. In summary, completion of the strong Research Training Plan together with the Career
Development Plan will help prepare the applicant for a career as an independent scientist. The proposed
research will lead to significant advances in understanding mitochondrial Ca2+ uptake and will open potential
avenues for therapeutic intervention in diseases involving aberrant mitochondrial Ca2+ signaling.