Abstract

The investigators have analyzed the interactions of LPS with cells of the inflammatory process that can result in mortality in Gram-negative sepsis. A nontoxic lipid A derived from Rhodobacter sphaeroides (RsDPLA) that serves as a LPS antagonist in both in vivo and in vivo experimental conditions was developed. RsDPLA has the potential to be a key therapeutic adjunct to antagonize the initiating stimulus in Gram-negative sepsis, and is also a tool to study LPS-induced signal transduction. The investigators propose to: a) develop a novel, purified, and well characterized LPS crosslinking agent that will allow us to evaluate the interaction of LPS with macrophage membrane protein(s) other than CD14; b) test the hypothesis that RsDPLA blocks the interaction of LPS with a membrane-associated protein that is distinct from CD14; c) show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinases and mitogen-activated protein kinases (MAPK) are involved in the LPS-induced activation of Spl using RsDPLA and several pharmacologic inhibitors; and d) develop an effective therapeutic regimen in the pig septic shock model by using a combination of RsDPLA and other drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM050870-08
Application #
6385873
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
1994-05-15
Project End
2001-05-31
Budget Start
2001-05-01
Budget End
2001-05-31
Support Year
8
Fiscal Year
2001
Total Cost
$23,743
Indirect Cost

  Institution

Name
University of Wisconsin Madison
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715

  Publications

Qureshi, Asaf A; Zuvanich, Eleanor G; Khan, Dilshad A et al. (2018) Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs. Lipids Health Dis 17:62
Qureshi, Asaf A; Khan, Dilshad A; Mushtaq, Shahida et al. (2018) ?-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling pathways in chronic hepatitis C patients. Lipids Health Dis 17:167
Silswal, Neerupma; Reis, Julia; Qureshi, Asaf A et al. (2017) Of Mice and Men: Proteasome's Role in LPS-Induced Inflammation and Tolerance. Shock 47:445-454
Qureshi, Asaf A; Khan, Dilshad A; Mahjabeen, Wajiha et al. (2013) Nutritional Supplement-5 with a Combination of Proteasome Inhibitors (Resveratrol, Quercetin, ?-Tocotrienol) Modulate Age-Associated Biomarkers and Cardiovascular Lipid Parameters in Human Subjects. J Clin Exp Cardiolog 4:
Qureshi, Asaf A; Khan, Dilshad A; Mahjabeen, Wajiha et al. (2012) Suppression of Nitric Oxide Production and Cardiovascular Risk Factors in Healthy Seniors and Hypercholesterolemic Subjects by a Combination of Polyphenols and Vitamins. J Clin Exp Cardiolog S5:8
Beasley, Ashley S; Cotter, Robert J; Vogel, Stefanie N et al. (2012) A variety of novel lipid A structures obtained from Francisella tularensis live vaccine strain. Innate Immun 18:268-78
Liu, Xun; Silverstein, Peter S; Singh, Vijeta et al. (2012) Methamphetamine increases LPS-mediated expression of IL-8, TNF-? and IL-1? in human macrophages through common signaling pathways. PLoS One 7:e33822
Qureshi, Nilofer; Morrison, David C; Reis, Julia (2012) Proteasome protease mediated regulation of cytokine induction and inflammation. Biochim Biophys Acta 1823:2087-93
Qureshi, Asaf A; Guan, Xiu Qin; Reis, Julia C et al. (2012) Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids Health Dis 11:76
Rockwell, Cheryl E; Monaco, John J; Qureshi, Nilofer (2012) A critical role for the inducible proteasomal subunits LMP7 and MECL1 in cytokine production by activated murine splenocytes. Pharmacology 89:117-26

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