In this .project, we have been testing the hypothesis that neuroinflammation contributes to neurodegeneration in vivo and that targeting selective glial activation pathways linked to disease-relevant endpoints will suppress neuroinflammation and provide neuroprotection. We emphasize throughout this application by concrete examples how our work has contributed to a better understanding of molecular mechanisms underlying neuroinflammation, how our in vivo studies have validated the relationship between chronic glial activation and neuronal dysfunction/death, and how our in vivo (integrated) chemical biology research has demonstrated that targeting neuroinflammatory signaling pathways is a viable approach to development of future therapeutics for Alzheimer's disease (AD). Our work over the last four years has contributed substantially to the increasing appreciation of the field that neuroinflammation plays a key role in the progression of pathology in neurodegenerative diseases, and we are committed and eager to continue our work in this area. Finally, MERIT grant awardees are expected to be leaders in their disciplines, and to increase their visibility and contributions to the field during the time of the award. During the last four years, I believe that this has been the case in terms of my contributions to the area of neuroinflammation and AD.
The specific aims of the current funding period relate to this two-pronged research effort of defining mechanisms and developing strategies for modulation of glial activation. The goal of aim 1 was elucidation of molecular mechanisms of glial activation induced by beta-amyloid 1-42 (A(3) as the prototypical AD-relevant, glial activating stimulus. The goal of aim 2 was to develop strategies to modulate glial activation pathways that lead to detrimental responses and examine the consequences to neuronal function

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG013939-14
Application #
7628966
Study Section
Special Emphasis Panel (NSS)
Program Officer
Petanceska, Suzana
Project Start
1996-09-19
Project End
2010-06-30
Budget Start
2009-07-15
Budget End
2010-06-30
Support Year
14
Fiscal Year
2009
Total Cost
$194,409
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Barone, Eugenio; Di Domenico, Fabio; Sultana, Rukhsana et al. (2012) Heme oxygenase-1 posttranslational modifications in the brain of subjects with Alzheimer disease and mild cognitive impairment. Free Radic Biol Med 52:2292-301
Sultana, Rukhsana; Robinson, Renã A S; Di Domenico, Fabio et al. (2011) Proteomic identification of specifically carbonylated brain proteins in APP(NLh)/APP(NLh) × PS-1(P264L)/PS-1(P264L) human double mutant knock-in mice model of Alzheimer disease as a function of age. J Proteomics 74:2430-40
Thompson, Wendy L; Van Eldik, Linda J (2009) Inflammatory cytokines stimulate the chemokines CCL2/MCP-1 and CCL7/MCP-3 through NFkB and MAPK dependent pathways in rat astrocytes [corrected]. Brain Res 1287:47-57
Chico, Laura K; Van Eldik, Linda J; Watterson, D Martin (2009) Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 8:892-909
Thompson, Wendy L; Karpus, William J; Van Eldik, Linda J (2008) MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflammation 5:35
Fuller, Abby D; Van Eldik, Linda J (2008) MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol 3:246-56
Borders, Aaron S; de Almeida, Lucia; Van Eldik, Linda J et al. (2008) The p38alpha mitogen-activated protein kinase as a central nervous system drug discovery target. BMC Neurosci 9 Suppl 2:S12
Lloyd, Eric; Somera-Molina, Kathleen; Van Eldik, Linda J et al. (2008) Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury. J Neuroinflammation 5:28
Van Eldik, Linda J; Thompson, Wendy L; Ralay Ranaivo, Hantamalala et al. (2007) Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches. Int Rev Neurobiol 82:277-96
Wing, Laura K; Behanna, Heather A; Van Eldik, Linda J et al. (2006) De novo and molecular target-independent discovery of orally bioavailable lead compounds for neurological disorders. Curr Alzheimer Res 3:205-14

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