Nitric oxide (NO) is one of the smallest molecules in Nature and has recently been discovered to play important roles in a remarkable array of physiological and pathophysiological phenomena. In spite of the fact that it is extremely small, as cellular molecules go, its actions are multiple and not well understood. In many cases, its actions are """"""""Janus-faced"""""""", performing either harmful or helpful actions. What controls this contradictory behavior is unknown. We propose to study one important role of NO, as a messenger molecule that initiates signaling cascades resulting in appropriate responses of the cell. NO has been proposed to effect a variety of signaling mechanisms, and we have chosen to examine the roles of NO in tumor development. NO is well- known to possess pro-cancerous and also anti-cancerous actions. We will apply a new theoretical approach to this problem, which makes specific and testable predictions. Our studies will range from test-tube chemistry of simple small molecules to isolated signaling proteins to the activation of these proteins in cells and finally the importance of NO signaling in an animal tumor model. We hope to develop a biochemical """"""""road map"""""""" that could navigate design of specific therapeutic modalities to allow intelligent manipulation of prevailing in vivo chemical conditions and/or protein responses and effect redirection of the """"""""pro-cancerous"""""""" biological actions toward the """"""""anti- cancerous"""""""".

Public Health Relevance

The research we will carry out is directed to understand the mechanisms between cells that orchestrate the development of Cancer. Our overall approach is to try to understand the chemistry that determines signaling by the very small and reactive molecule nitric oxide (NO). Our experimental systems will span """"""""test-tube"""""""" studies with small molecules to cells and proteins and finally to studies using a tumor model in mice. Insights we obtain may form the basis for the development of new therapies for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131653-05
Application #
8458894
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
2009-03-27
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$278,595
Indirect Cost
$79,180
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Lancaster Jr, Jack R (2015) Nitric oxide: a brief overview of chemical and physical properties relevant to therapeutic applications. Future Sci OA 1:FSO59
Li, Qian; Li, Chuanyu; Mahtani, Harry K et al. (2014) Nitrosothiol formation and protection against Fenton chemistry by nitric oxide-induced dinitrosyliron complex formation from anoxia-initiated cellular chelatable iron increase. J Biol Chem 289:19917-27
Meares, Gordon P; Fontanilla, Dominique; Broniowska, Katarzyna A et al. (2013) Differential responses of pancreatic β-cells to ROS and RNS. Am J Physiol Endocrinol Metab 304:E614-22
Li, Qian; Lancaster Jr, Jack R (2013) Chemical foundations of hydrogen sulfide biology. Nitric Oxide 35:21-34
Stapley, Ryan; Owusu, Benjamin Y; Brandon, Angela et al. (2012) Erythrocyte storage increases rates of NO and nitrite scavenging: implications for transfusion-related toxicity. Biochem J 446:499-508
Adgent, Margaret A; Squadrito, Giuseppe L; Ballinger, Carol A et al. (2012) Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications. Free Radic Biol Med 53:951-61
Zhang, Dehui; Devarie-Baez, Nelmi O; Li, Qian et al. (2012) Methylsulfonyl benzothiazole (MSBT): a selective protein thiol blocking reagent. Org Lett 14:3396-9
Farhana, Aisha; Saini, Vikram; Kumar, Ashwani et al. (2012) Environmental heme-based sensor proteins: implications for understanding bacterial pathogenesis. Antioxid Redox Signal 17:1232-45
Hill, Bradford G; Benavides, Gloria A; Lancaster Jr, Jack R et al. (2012) Integration of cellular bioenergetics with mitochondrial quality control and autophagy. Biol Chem 393:1485-1512
Li, Qian; Lancaster Jr, Jack R (2012) A Conspectus of Cellular Mechanisms of Nitrosothiol Formation from Nitric Oxide. For Immunopathol Dis Therap 3:183-191

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