Abstract

Small organic molecules also continue to be of great utility as biological tools for the identification and characterization of new targets and inhibitory or stimulatory mechanisms, as well as for low-cost large-scale therapeutic applications. Our Core provides unique small molecule synthesis and analysis capabilities based on innovative medicinal chemistry and analytical procedures to the CMCR, and we have a successful track record for working synergistically in developing novel tool compounds and therapeutic candidates for radiation mitigation.
Our specific aims are: 1. To synthesize labeled (fluorescent-and isotope-labeled) variants of (a) necrostatin-1, (b) MMS350, (c) varespladib, and (d) R-BEL for Projects 1, 3 and 4 as well as Core H. 2. To supply Project 1 and Core G with scaled-up quantities of BODIPY-JP4-039 and MMS-350. 3. To supply Project 2 with lipid mediators, including homologs of cardiolipins. 4. To supply Projects 1, 2 and 3 with (a) imidazole fatty acid derivatives, (b) MitoEbselen-2, and (c) hepoxillin-A3 and analogs thereof; and 5. To perform EPR and HPLC analyses with either direct electrochemical detection of the analytes or, following tissue extraction, FL detection after derivatization with fluorophores.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI068021-13
Application #
9323249
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2005-09-30
Project End
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
13
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Knickelbein, Kyle; Tong, Jingshan; Chen, Dongshi et al. (2018) Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene 37:4599-4610
Wei, Liang; Leibowitz, Brian J; Epperly, Michael et al. (2018) The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice. Sci Rep 8:2072
Christner, Susan; Guo, Jianxia; Parise, Robert A et al. (2018) Liquid chromatography-tandem mass spectrometric assay for the quantitation of the novel radiation protective agent and radiation mitigator JP4-039 in murine plasma. J Pharm Biomed Anal 150:169-175
Wang, Yi-Jun; Fletcher, Rochelle; Yu, Jian et al. (2018) Immunogenic effects of chemotherapy-induced tumor cell death. Genes Dis 5:194-203
Chen, Dongshi; Tong, Jingshan; Yang, Liheng et al. (2018) PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci U S A 115:3930-3935
Chen, Dongshi; Ni, Hong-Min; Wang, Lei et al. (2018) PUMA induction mediates acetaminophen-induced necrosis and liver injury. Hepatology :
Chao, Honglu; Anthonymuthu, Tamil S; Kenny, Elizabeth M et al. (2018) Disentangling oxidation/hydrolysis reactions of brain mitochondrial cardiolipins in pathogenesis of traumatic injury. JCI Insight 3:
Steinman, Justin; Epperly, Michael; Hou, Wen et al. (2018) Improved Total-Body Irradiation Survival by Delivery of Two Radiation Mitigators that Target Distinct Cell Death Pathways. Radiat Res 189:68-83
Lou, Wenjia; Ting, Hsiu-Chi; Reynolds, Christian A et al. (2018) Genetic re-engineering of polyunsaturated phospholipid profile of Saccharomyces cerevisiae identifies a novel role for Cld1 in mitigating the effects of cardiolipin peroxidation. Biochim Biophys Acta Mol Cell Biol Lipids 1863:1354-1368
Anthonymuthu, Tamil S; Kenny, Elizabeth M; Lamade, Andrew M et al. (2018) Oxidized phospholipid signaling in traumatic brain injury. Free Radic Biol Med 124:493-503

Showing the most recent 10 out of 203 publications