After spinal cord injury (SCI), the injury site is filled with cellular debris, especially myelin debris that creates a very unique lipid-dense environment. Macrophages are the predominant phagocyte that are responsible for debris-clearance, but this process is not only inefficient, it is also maladaptive. The excessive amount of myelin debris present at the injury site leads to formation lipid-laden macrophages (a.k.a. foamy macrophages) that become pro-inflammatory and contribute to tissue regeneration failure. In addition to macrophages, microglia and fibroblasts also become foam cells. Therefore, understanding the mechanisms of myelin debris uptake and catabolism after SCI may lead to novel therapeutic targets to promote repair after SCI. In this application, we will investigate the mechanism of myelin debris uptake as well as the export of its catabolic byproduct in macrophages, microglia, and fibroblasts after SCI. In addition, we will test the therapeutic potential of novel nanoparticles that can target the uptake and efflux mechanisms.

Public Health Relevance

Patients with spinal cord injury (SCI) suffer from permanent disabilities but have limited treatment and therapeutic options. A major impediment to spinal cord regeneration is the failure to clear cellular debris at the injury site. Much of this debris is from myelin, which creates a very unique lipid-dense environment. Excessive uptake of lipid in phagocytic cells transforms them into inflammatory cells that contribute to the pathogenesis of SCI. Thus, we propose to investigate the mechanisms of lipid uptake and efflux in phagocytic cells at the injury site, and target these processes to limit formation of lipid-laden cells and promote tissue repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS081040-06A1
Application #
9614088
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Jakeman, Lyn B
Project Start
2012-09-01
Project End
2022-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Zhu, Yunjiao; Soderblom, Cynthia; Trojanowsky, Michelle et al. (2015) Fibronectin Matrix Assembly after Spinal Cord Injury. J Neurotrauma 32:1158-67
Lee, Do-Hun; Lee, Jae K (2013) Animal models of axon regeneration after spinal cord injury. Neurosci Bull 29:436-44

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