The central tenet to be investigated in this proposal is that nitric oxide (NO) is a cell signaling molecule and mediator of cytotoxicity is not just dependent upon its instantaneous concentration at a given point, but rather it is also dependent upon its concentration gradient. The protocols that are currently in use for NO research do not allow the spatial release of biologically relevant concentration gradients of NO, nor do they allow the direct temporal and spatial detection of NO with fine resolution. An important goal of this proposal is to develop novel fluorescent probes and donors that afford spatiotemporal detection of NO, and to develop new methods for well defined spatiotemporal release of NO. To achieve a greater understanding of the role of NO gradients in mediating cell signaling and cytotoxicity, the research conducted in this COBRE IDeA proposal will vertically integrate five medically relevant research projects that employ unique but complementary experimental systems. These novel NO reagents will be used throughout this proposal and will be specifically used in this project to test the hypothesis that nitric oxide is a sperm chemotactic molecule. Because NO has been implicated in bowel dysfunction in the elderly, Project 2 will employ an aged rat model system to investigate whether alterations in neural and gastrointestinal NO signaling within the enteric nervous system of the bowel investigate whether alterations in neural and gastrointestinal NO signaling within the enteric nervous system of the bowel are involved. Project 3 will elucidate specific cell physiology, pathology, and signaling pathways involving NO production in the upper airway epithelium and its role in exacerbating and/or moderating disease caused by respiratory tract pathogens. Project 4 will investigate the role of NO in retrovirus-induced neurodegeneration using a murine retrovirus model. This investigation will provide insight into the potential role of NO in HV-induced neurological disease. Finally, Project 5 will examine the role of NO in controlling infection by obligate intracellular bacterial human pathogens. The bacterial response to NO stress will also be investigated. Not only will these studies lead to the development of novel NO release and detection reagents with broad scale applicability, they will also provide a greater understanding of the role of NO as a signaling molecule, and as protective or damaging factor in the progression of human disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory Grants (P20)
Project #
5P20RR015553-05
Application #
6788788
Study Section
Special Emphasis Panel (ZRR1-RCMI-2 (01))
Program Officer
Taylor, Fred
Project Start
2000-09-15
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$1,067,446
Indirect Cost
Name
University of Wyoming
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
069690956
City
Laramie
State
WY
Country
United States
Zip Code
82071
Panzhinskiy, E; Hua, Y; Culver, B et al. (2013) Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes. Diabetologia 56:598-607
Wang, Xinjun; Sun, Qian-Quan (2012) Characterization of axo-axonic synapses in the piriform cortex of Mus musculus. J Comp Neurol 520:832-47
Hubbard, Catherine S; Rose, James D (2012) Brainstem neuronal and behavioral activation by corticotropin-releasing hormone depend on the behavioral state of the animal. Horm Behav 61:121-33
Dong, F; Skinner, D C; Wu, T John et al. (2011) The heart: a novel gonadotrophin-releasing hormone target. J Neuroendocrinol 23:456-63
Jiao, Yuanyuan; Zhang, Zhi; Zhang, Chunzhao et al. (2011) A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo. Proc Natl Acad Sci U S A 108:12131-6
Hubbard, Catherine S; Dolence, E Kurt; Rose, James D (2010) Brainstem reticulospinal neurons are targets for corticotropin-releasing factor-Induced locomotion in roughskin newts. Horm Behav 57:237-46
Skinner, D C; Albertson, A J; Navratil, A et al. (2009) Effects of gonadotrophin-releasing hormone outside the hypothalamic-pituitary-reproductive axis. J Neuroendocrinol 21:282-92
Davis, J D; Barrett, S F; Wright, C H G et al. (2009) A bio-inspired apposition compound eye machine vision sensor system. Bioinspir Biomim 4:046002
Hubbard, Catherine S; Dolence, E Kurt; Shires, Joel A et al. (2009) Identification of brain target neurons using a fluorescent conjugate of corticotropin-releasing factor. J Chem Neuroanat 37:245-53
Riley, D T; Harmann, W M; Barrett, S F et al. (2008) Musca domestica inspired machine vision sensor with hyperacuity. Bioinspir Biomim 3:026003

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