The long-term goal of this research is to track the time- and position-dependent flux of labile zinc in the central nervous system. Zinc stored in vesicles at presynaptic glutamatergic neurons in the hippocampus is released upon physiological stimulation to perform an undefined role in neurotransmission. Uncontrolled Zn2+ release in the brain is associated with damage following seizure, ischemia, and blunt head trauma. In order to study these neurochemical phenomena, zinc- responsive sensors will be prepared, characterized, and introduced into cells, including primary neuron cultures, and brain tissue to quantify Zn2+ stores, identify its targets, and track its mobilization under functional and pathological conditions. The design, synthesis, characterization, and utilization of the sensors constitute a major component of this research project. Each sensor will have up to three modules. Minimally, there will be zinc-binding and zinc-reporting units. The binding module typically comprises multidentate ligands with variable Zn2+ affinity, selectivity for Zn2+ over competing ions in neuronal tissue, and fast, reversible coordination to monitor biological changes on the msec time scale. The zinc-reporting module will be a fluorophore, for use in wide- field and confocal microscopy, that responds to the bound ion. The reporters are mostly fluorescein and related constructs because of their brightness, photostability, and long excitation and emission wavelengths, but fluorescent p-conjugated polymers will also be pursued. Sensors for monitoring zinc by magnetic resonance imaging (MRI) are proposed as well. Despite lower resolution, MRI has the advantage that it can be applied in live animals. Both zinc-responsive manganese(lll) porphyrin and salen constructs are introduced for this aspect of the proposal. Strategies are adopted for attaching an optional third module to localize a fluorescence- or MRI-based zinc sensor to specific cellular targets. In this manner, the sensors can be used to investigate Zn2+ dynamics at glutamatergic receptors on postsynaptic neurons and at intracellular organelles following physiological or pathological stimulation. This project is relevant to public health, for it will provide information to test theories about the functions of Zn2+ in the brain as well as the means by which to evaluate the postulated association of uncontrolled zinc levels with neurodegenerative diseases, such as Alzheimer's, and with more acute toxic encephalopathies. The chemistry devised will also facilitate the development of tools to measure free zinc (pZn) in vivo and may assist in the formulation of strategies for diagnosing, treating, and preventing Zn2+-induced neurological damage. ? ? ?
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| Goldberg, Jacob M; Lippard, Stephen J (2017) Challenges and Opportunities in Brain Bioinorganic Chemistry. Acc Chem Res 50:577-579 |
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| Goldberg, Jacob M; Loas, Andrei; Lippard, Stephen J (2016) Metalloneurochemistry and the Pierian Spring: 'Shallow Draughts Intoxicate the Brain'. Isr J Chem 56:791-802 |
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| Rivera-Fuentes, Pablo; Wrobel, Alexandra T; Zastrow, Melissa L et al. (2015) A Far-Red Emitting Probe for Unambiguous Detection of Mobile Zinc in Acidic Vesicles and Deep Tissue. Chem Sci 6:1944-1948 |
| Zhang, Daniel Y; Azrad, Maria; Demark-Wahnefried, Wendy et al. (2015) Peptide-based, two-fluorophore, ratiometric probe for quantifying mobile zinc in biological solutions. ACS Chem Biol 10:385-9 |
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