Fluorescent Copper Probes for Intracellular Imaging

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DESCRIPTION (provided by applicant): Copper is an essential trace element, which is critical to human health. The redox properties of copper require a sophisticated management to avoid oxidative damage of lipids, proteins or DNA. Therefore the cell must maintain a subtle balance, such that copper is available for catalytic processes, but at the same time avoid accumulation to toxic levels. The detailed mechanisms and cellular structures responsible for maintaining control of intracellular copper levels are not well understood. This information is critical for the understanding of the molecular mechanisms of diseases caused by copper imbalance, such as Wilson's or Menkes' disease, both of which are fatal. More recently, certain neurological disorders including ALS and Alzheimer's disease have been linked to disorders in copper metabolism. One of the central hypotheses of the copper regulatory machinery suggests the presence of intracellular storage or buffer sites as a defense against deficiency, but also to protect the cell from abnormally high concentrations of copper. Golgi secretory vesicles which contain a copper ATPase membrane protein might function as intracellular compartments for copper storage. Fluorescence probes, which can permeate the plasma membrane are powerful tools for the study of intracellular metal ion distributions, yet rigorous analytical techniques for sensitive in vivo measurements of intracellular copper levels are completely lacking. The goal of the proposed project is the development of a copper specific fluorescent probe, which would not only allow to monitor vesicular labile copper concentrations, but would also provide information about the subcellular distribution in cell lines with disorders in copper metabolism. In a larger context a copper specific fluorescent probe will be of great importance for the long-term development of novel diagnostic and therapeutic tools for copper related human diseases.