This continuation renewal seeks support for years 6-10 for our Center of Biomedical Research Excellence (COBRE) in Oxidants, Redox Balance, and Stress Signaling at the Medical University of South Carolina (MUSC). Investigator projects focus on human pathologies that include many of the perceived strengths of MUSC including, cancer, cardiovascular disease, neurodegenerative disorders and drug/alcohol addiction and have additional components of drug discovery and development. In each instance the interface of these diseases with oxidant stress, redox homeostasis and stress signaling provides the fundamentals for the programmatic development of the Center. We plan to develop these assets further via clusters of 5 projects and 5 Cores involving 10 established scientists from 4 academic disciplines, with project Directors being from 4 different departments from 2 colleges. Because of increased demand and at the behest of our EAC, we have added a new core (Analytical Redox), in concert to the existing facilities (Proteomics, Cell and Molecular Imaging, Bioenergetics Profiling, Administrative). The COBRE has a number of faculty members who have graduated following successful grant awards garnered in years 1-4, most of whom remain affiliated with the program. Research projects for the five target mentees cover: resistance to drugs that target the proteasome in multiple myeloma, redox regulation of cancer stem cell growth, ROS in mitochondrial anion channel functions, ROS in mitochondrial function in aortic valve stenosis and antioxidants in vagus nerve stimulation in Parkinson's disease. Mentoring and career development efforts also provide critical mass in sustaining scientific growth and development of independent research careers through the COBRE. As with the previous period as junior faculty members achieve success, there are plans for the COBRE Directors to recruit between 3 and 6 individuals over the next five years, providing a cadre of new investigators eligible for the COBRE program. This COBRE includes cross-college and inter-department collaborations, with the Directors having leadership roles in the Colleges of Medicine and Pharmacy, the Hollings Cancer Center and South Carolina Center for Therapeutic Discovery and Development. This incorporates the recruitment of endowed chairs that can participate as mentors and laboratory space in the Drug Discovery Building. During Phase I, we have partnered with COBRE's from the University of South Carolina (USC) and Nebraska to foster teaching, research collaborations and technical expertise. Our Phase II COBRE will continue to emphasize the efforts of junior faculty, to expand and sharpen their research programs. Independent research projects and proposals, robust interactions among established investigators in oxidative stress signaling, along with effective mentoring will continue to be the overriding goals for this COBRE renewal.

Public Health Relevance

While oxygen provides the most efficient way to produce energy through oxidative phosphorylation, paradoxically it also produces toxic byproducts. Through adaptation, organisms have evolved numerous redox- based stress pathways to counteract this toxicity. In human diseases, these pathways can sometimes malfunction leading to a broad range of human maladies. This COBRE seeks to support faculty and their research in these areas, to build a sustainable Center that can provide a focal effort to comprehend the integral importance of redox stress signaling in human diseases and the treatment thereof.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM103542-06
Application #
9149869
Study Section
Special Emphasis Panel (ZGM1-RCB-6 (C2))
Program Officer
Zlotnik, Hinda
Project Start
2011-09-01
Project End
2021-07-31
Budget Start
2016-09-01
Budget End
2017-07-31
Support Year
6
Fiscal Year
2016
Total Cost
$2,242,500
Indirect Cost
$742,500
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Zhang, Jie; Ye, Zhi-Wei; Singh, Shweta et al. (2018) An evolving understanding of the S-glutathionylation cycle in pathways of redox regulation. Free Radic Biol Med 120:204-216
Li, Xiaoyang; Peterson, Yuri K; Inks, Elizabeth S et al. (2018) Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 Status. J Med Chem 61:2589-2603
Kim, Mi Jin; Vargas, Marcelo R; Harlan, Benjamin A et al. (2018) Nitration and Glycation Turn Mature NGF into a Toxic Factor for Motor Neurons: A Role for p75NTR and RAGE Signaling in ALS. Antioxid Redox Signal 28:1587-1602
Fang, Diana; Maldonado, Eduardo N (2018) VDAC Regulation: A Mitochondrial Target to Stop Cell Proliferation. Adv Cancer Res 138:41-69
Klauber-DeMore, Nancy; Schulte, Bradley A; Wang, Gavin Y (2018) Targeting MYC for triple-negative breast cancer treatment. Oncoscience 5:120-121
Chatterjee, Shilpak; Daenthanasanmak, Anusara; Chakraborty, Paramita et al. (2018) CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab 27:85-100.e8
Gibbs, Whitney S; Garrett, Sara M; Beeson, Craig C et al. (2018) Identification of dual mechanisms mediating 5-hydroxytryptamine receptor 1F-induced mitochondrial biogenesis. Am J Physiol Renal Physiol 314:F260-F268
Nunes, Shirleide Santos; Fernandes, Renata Salgado; Cavalcante, Carolina Henriques et al. (2018) Influence of PEG coating on the biodistribution and tumor accumulation of pH-sensitive liposomes. Drug Deliv Transl Res :
Monteiro, Liziane O F; Fernandes, Renata S; Oda, Caroline M R et al. (2018) Paclitaxel-loaded folate-coated long circulating and pH-sensitive liposomes as a potential drug delivery system: A biodistribution study. Biomed Pharmacother 97:489-495
Womersley, Jacqueline S; Townsend, Danyelle M; Kalivas, Peter W et al. (2018) Targeting redox regulation to treat substance use disorder using N-acetylcysteine. Eur J Neurosci :

Showing the most recent 10 out of 109 publications