This research will investigate to what extent the reparative potential of macrophages exists within the traumatically injured spinal cord. Historically, macrophages have been considered inflammatory scavenger cells in the CNS, capable only of removing cellular debris at sites of injury or infection. Now, many functions have been attributed to these cells including the ability to promote blood vessel growth, myelination, and neurite sprouting/regeneration. Unfortunately, these same cells can promote demyelination and cell injury. How and under what conditions macrophages effect such a broad range of biological functions is not clear, but may result from changes in the lesion microenvironment. It is the major hypothesis of this proposal that the inherent ability of macrophages to promote tissue repair and functional recovery changes as a function of time after spinal cord injury (SCI) and is negatively influenced by the accumulation of blood-borne elements (cells and proteins) at the injury site. Using radiation bone marrow chimeric rats in combination with macrophage and complement-depletion protocols, we will examine how these vascular constituents influence resident (microglia) and recruited (blood-derived) macrophage activation and function. Specifically, the neurotrophic and oxidative capacity of each macrophage subpopulation will be evaluated in vivo using immunohistochemistry and in vitro using cytokines and other factors present in the injury site to trigger macrophage effector functions. Cells exhibiting neurotrophic secretory profiles will be transplanted into injured rat spinal cords to test their ability to promote regeneration and functional recovery. By learning more about the factors that influence macrophage function in the injured CNS, we may be able to harness the innate reparative potential of the inflammatory response (specifically macrophages) to promote functional regeneration. Moreover, we will be determining the feasibility of manipulating an intrinsic component of the injury site to promote tissue repair. Such an approach may be biologically and clinically advantageous and could eliminate the need for chronic drug therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS037846-03S1
Application #
6484388
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Kleitman, Naomi
Project Start
1999-04-05
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
3
Fiscal Year
2001
Total Cost
$43,365
Indirect Cost
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Gensel, John C; Wang, Yan; Guan, Zhen et al. (2015) Toll-Like Receptors and Dectin-1, a C-Type Lectin Receptor, Trigger Divergent Functions in CNS Macrophages. J Neurosci 35:9966-76
Lerch, Jessica K; Puga, Denise A; Bloom, Ona et al. (2014) Glucocorticoids and macrophage migration inhibitory factor (MIF) are neuroendocrine modulators of inflammation and neuropathic pain after spinal cord injury. Semin Immunol 26:409-14
Alexander, Jessica K; Cox, Gina M; Tian, Jin-Bin et al. (2012) Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress. Exp Neurol 236:351-62
Kigerl, Kristina A; Ankeny, Daniel P; Garg, Sanjay K et al. (2012) System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo. Exp Neurol 233:333-41
Benowitz, Larry I; Popovich, Phillip G (2011) Inflammation and axon regeneration. Curr Opin Neurol 24:577-83
Gilbert, Ryan J; Rivet, Christopher J; Zuidema, Jonathan M et al. (2011) Biomaterial design considerations for repairing the injured spinal cord. Crit Rev Biomed Eng 39:125-80
Donnelly, Dustin J; Longbrake, Erin E; Shawler, Todd M et al. (2011) Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci 31:9910-22
Gensel, John C; Donnelly, Dustin J; Popovich, Phillip G (2011) Spinal cord injury therapies in humans: an overview of current clinical trials and their potential effects on intrinsic CNS macrophages. Expert Opin Ther Targets 15:505-18
Awad, Hamdy; Ankeny, Daniel P; Guan, Zhen et al. (2010) A mouse model of ischemic spinal cord injury with delayed paralysis caused by aortic cross-clamping. Anesthesiology 113:880-91
Gensel, John C; Schonberg, David L; Alexander, Jessica K et al. (2010) Semi-automated Sholl analysis for quantifying changes in growth and differentiation of neurons and glia. J Neurosci Methods 190:71-9

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