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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067169-02
Application #
6877055
Study Section
Metallobiochemistry Study Section (BMT)
Program Officer
Preusch, Peter C
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$190,214
Indirect Cost
Name
Georgia Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Morgan, M Thomas; Yang, Bo; Harankhedkar, Shefali et al. (2018) Stabilization of Aliphatic Phosphines by Auxiliary Phosphine Sulfides Offers Zeptomolar Affinity and Unprecedented Selectivity for Probing Biological CuI. Angew Chem Int Ed Engl 57:9711-9715
Bourassa, Daisy; Elitt, Christopher M; McCallum, Adam M et al. (2018) Chromis-1, a Ratiometric Fluorescent Probe Optimized for Two-Photon Microscopy Reveals Dynamic Changes in Labile Zn(II) in Differentiating Oligodendrocytes. ACS Sens 3:458-467
Morgan, M Thomas; Nguyen, Lily Anh H; Hancock, Haylie L et al. (2017) Glutathione limits aquacopper(I) to sub-femtomolar concentrations through cooperative assembly of a tetranuclear cluster. J Biol Chem 292:21558-21567
Morgan, M T; McCallum, A; Fahrni, C J (2016) Rational Design of a Water-Soluble, Lipid-Compatible Fluorescent Probe for Cu(I) with Sub-Part-Per-Trillion Sensitivity. Chem Sci 7:1468-1473
Friscourt, Frédéric; Fahrni, Christoph J; Boons, Geert-Jan (2015) Fluorogenic Strain-Promoted Alkyne-Diazo Cycloadditions. Chemistry 21:13996-4001
Morgan, M Thomas; Sumalekshmy, S; Sarwar, Mysha et al. (2014) Probing ternary complex equilibria of crown ether ligands by time-resolved fluorescence spectroscopy. J Phys Chem B 118:14196-202
Fahrni, Christoph J (2013) Synthetic fluorescent probes for monovalent copper. Curr Opin Chem Biol 17:656-62
Bagchi, Pritha; Morgan, M Thomas; Bacsa, John et al. (2013) Robust affinity standards for Cu(I) biochemistry. J Am Chem Soc 135:18549-59
McRae, Reagan; Lai, Barry; Fahrni, Christoph J (2013) Subcellular redistribution and mitotic inheritance of transition metals in proliferating mouse fibroblast cells. Metallomics 5:52-61
Morgan, M Thomas; Bagchi, Pritha; Fahrni, Christoph J (2013) High-contrast fluorescence sensing of aqueous Cu(I) with triarylpyrazoline probes: dissecting the roles of ligand donor strength and excited state proton transfer. Dalton Trans 42:3240-8

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