CIMED has awarded two Pilot and Feasibility grants for 2015

Peng Yuan, Ph.D.
Assistant Professor, Cell Biology & Physiology

“Molecular Mechanisms of Copper Homeostasis”

Copper is a trace element of vital importance in human physiology, with many enzymes using copper as an essential cofactor to perform their specific work. Copper homeostasis is fundamental to many critical physiological processes including liver function and the development of the heart, the central nervous system, and the immune system. Imbalance of copper levels in the body causes serious problems in human health. The major players in copper uptake and distribution in the human body include the high-affinity copper transporter CTR1 and the coppertransporting ATPases ATP7A and ATP7B, which are integral membrane proteins. How these proteins transport copper across cell membranes is poorly understood because there are no highresolution three-dimensional structures of these copper transporters. Without detailed pictures of these transporter proteins at atomic resolutions, we cannot understand how they move copper ions across cell membranes and how mutations affect function and cause diseases.

This application combines X-ray crystallography, biochemistry, and electrophysiology to investigate the molecular mechanisms of copper homeostasis. Specifically, we plan to determine atomic-resolution crystal structures of the major players in copper metabolism CTR1, ATP7A, and ATP7B. Recent advances include the large-scale expression, purification, and crystallization of CTR1 proteins in my laboratory. We will use biochemical assays to study the copper-transport mechanisms and the underlying mechanisms of disease-associated mutations. Structural and biochemical analyses of these transporters will advance our understanding of cellular copper homeostasis. In addition, it will provide key information for the development of rational, mechanismbased therapies for the treatment of these copper-related diseases including Menkes disease, Wilson’s disease, occipital horn syndrome, and distal motor neuropathy.

 

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Kendall J. Blumer, Ph.D.
Professor, Cell Biology & Physiology

Michael Bruchas, Ph.D.
Assistant Professor, Departments of Anesthesiology, Anatomy/Neurobiology

“Targeting signaling protein palmitoylation to enhance opioid analgesia”

The goal of this collaborative pilot project is to determine for the first time whether intracellular enzymes that mediate palmitoylation turnover constitute a novel class of druggable targets to enhance opioid analgesia or blunt opioid tolerance. Moreover, this project addresses a key question in basic science: whether palmitoylation turnover, like phosphorylation, controls cell signaling in vivo.  Successful completion of this project will set the stage for obtaining NIH funding aimed at: i) identifying mechanisms whereby palmitoylation turnover enzymes target components of the opioid signaling system to regulate analgesia and/or tolerance, and ii) developing selective small molecule inhibitors or activators of palmitoylation turnover enzymes as chemical probes and lead compounds for drug discovery of opioid “sensitizers” in pain therapy.