This proposal describes a 5-year program (2 years mentored, 3 years independent) for the development of an academic career in cardiovascular disease and trauma pathophysiology research with an emphasis on ion channel function and Ca2+ signaling pathways. Dr. Collier (the applicant) has a background in ion channel structure and function, biochemistry, and molecular biology. He competed his doctoral training in the Department of Molecular Physiology & Biophysics at the University of Iowa under the mentorship of Dr. Peter Snyder. He came to the University of Vermont as Postdoctoral Associate to develop new skills in Ca2+ imaging, vascular biology, and animal models of traumatic injury to aid his transition toward becoming an independent investigator. The University of Vermont (UVM) is internationally recognized for its strength in pharmacology, with unique expertise in Ca2+ signaling, vascular biology, and trauma. Mark Nelson, Ph.D. will mentor Dr. Collier's scientific development and transition to independence. Dr. Nelson is a recognized leader in the field of Ca2+ signaling and vascular biology. Dr. Nelson has trained numerous postdoctoral fellows and graduate students, many of whom are now established independent investigators. Kalev Freeman, M.D., Ph.D. will co-mentor Dr. Collier. Dr. Freeman provides unique clinical perspective and expertise in trauma pathophysiology. This research environment maximizes the potential for Dr. Collier to establish a scientific niche from which an academic career can be constructed. This project will facilitate continued technical, intellectual, and professional training which will help Dr. Collier develop a unique skill set that will allow him to establish an independent laboratory at an academic research institution of his choosing. Traumatic injury is a major public health problem. Trauma accounts for 37 million hospital visits and is estimated to cost the U.S. more than $700 billion each year. Traumatic brain injury (TBI) accounts for 1.7 million hospital visits and often leaves survivors suffering from cardiovascular complications such as hypertension, hypotension, coagulopathy, and stroke. The mechanism of these systemic complications is unknown. It has been demonstrated that traumatic injury releases toxic intracellular components into the systemic circulation, however, little is known about how these toxic factors affect tissue at the molecular level. This project will elucidate the basis of persistent altered endothelial cell function in systemic arteries following TBI, the mechanism by which trauma associated circulating factors induced endothelial cell Ca2+ signaling, and the basis of preservation of cerebral artery function following TBI.