This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The high toxicity of mercury compounds is well known, but the mechanisms of toxicity remain largely obscure. Human exposure to mercury comes from many sources, including predatory marine fish and from vaccines, where Thimerosal (ethylmercurithiosalicylate), a commonly-added fungicide and bactericide, has been implicated in autism and Asperger's syndrome. The nature and development of the toxic effects are critically dependent upon the chemical form of the mercury, but very little is known about the chemical fate of the metal after it has been ingested. One major reason for this is a lack of good in situ probes for mercury. X-ray absorption spectroscopy can provide information on the chemical environment of metals and metalloids in situ. We propose to apply Hg L-edge XAS to develop an understanding of the chemical toxicology of mercury in rats, as a model for human exposure. The ultimate goal of this work is to provide the chemical basis for effective chelation therapy treatment of mercury poisoning in humans. Current mercury chelation therapy drugs are not very effective. A striking illustration of their inadequacy is provided by the tragic case of a chemist at Dartmouth College, who was accidentally exposed to a small quantity of dimethylmercury and died ten months later despite intensive chelation therapy. The drugs currently used for mercury chelation therapy - dimercapto propanesulfonic acid, and dimercapto succinic acid - have their origins in antidotes for arsenic war agents such as Lewisite. While mercury is well known for its affinity for thiols, these viscinal dithiols are poorly suited as ligands for Hg due to their inability to coordinate the metal linearly. A knowledge of the chemical forms of mercury in tissues is an essential prerequisite for chelation therapy design, and we plan to use the information obtained from XAS, together with computational chemistry, to this end.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001209-28
Application #
7597955
Study Section
Special Emphasis Panel (ZRG1-BPC-E (40))
Project Start
2007-03-01
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
28
Fiscal Year
2007
Total Cost
$5,552
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Vickers, Chelsea; Liu, Feng; Abe, Kento et al. (2018) Endo-fucoidan hydrolases from glycoside hydrolase family 107 (GH107) display structural and mechanistic similarities to ?-l-fucosidases from GH29. J Biol Chem 293:18296-18308
Nguyen, Phong T; Lai, Jeffrey Y; Lee, Allen T et al. (2018) Noncanonical role for the binding protein in substrate uptake by the MetNI methionine ATP Binding Cassette (ABC) transporter. Proc Natl Acad Sci U S A 115:E10596-E10604
Aleman, Fernando; Tzarum, Netanel; Kong, Leopold et al. (2018) Immunogenetic and structural analysis of a class of HCV broadly neutralizing antibodies and their precursors. Proc Natl Acad Sci U S A 115:7569-7574
Herrera, Nadia; Maksaev, Grigory; Haswell, Elizabeth S et al. (2018) Elucidating a role for the cytoplasmic domain in the Mycobacterium tuberculosis mechanosensitive channel of large conductance. Sci Rep 8:14566
Lal, Neeraj K; Nagalakshmi, Ugrappa; Hurlburt, Nicholas K et al. (2018) The Receptor-like Cytoplasmic Kinase BIK1 Localizes to the Nucleus and Regulates Defense Hormone Expression during Plant Innate Immunity. Cell Host Microbe 23:485-497.e5
Pluvinage, Benjamin; Grondin, Julie M; Amundsen, Carolyn et al. (2018) Molecular basis of an agarose metabolic pathway acquired by a human intestinal symbiont. Nat Commun 9:1043
Beyerlein, Kenneth R; J├Ânsson, H Olof; Alonso-Mori, Roberto et al. (2018) Ultrafast nonthermal heating of water initiated by an X-ray Free-Electron Laser. Proc Natl Acad Sci U S A 115:5652-5657
Yoshizawa, Takuya; Ali, Rustam; Jiou, Jenny et al. (2018) Nuclear Import Receptor Inhibits Phase Separation of FUS through Binding to Multiple Sites. Cell 173:693-705.e22
Morrison, Christine N; Spatzal, Thomas; Rees, Douglas C (2017) Reversible Protonated Resting State of the Nitrogenase Active Site. J Am Chem Soc 139:10856-10862
Zhang, Haonan; Qiao, Anna; Yang, Dehua et al. (2017) Structure of the full-length glucagon class B G-protein-coupled receptor. Nature 546:259-264

Showing the most recent 10 out of 604 publications