Abstract

Spinal cord injury (SCI) results in formation of scar tissue that is a potent barrier to axon regeneration. This scar is comprised of excess deposition of extracellular matrix (ECM) molecules in both rodents and humans. Why most axons fail to grow into this ECM-rich region is not fully understood. In vitro assays have implicated fibroblasts as a major source of inhibitory ECM molecules, but whether this also true in vivo is not clear. While the meninges were thought to be the primary source of fibroblasts after SCI, recent evidence indicates that the perivascular niche could be an alternative source of the scar tissue. The overall goal of this proposal is to determine the role of perivascular fibroblasts in scar formation in order to promote axon regeneration after contusive SCI by pursuing the following aims: 1) Determine the temporospatial distribution and the cellular fate of fibroblasts after contusive SCI 2) Determine the effect of fibroblast ablation on scar formation and axon regeneration after SCI. 3) Determine the role of fibroblast PDGFR-? on scar formation and axon regeneration after SCI. Our proposed studies will fill a gap in knowledge about the role of fibroblasts in animal models of SCI and may reveal new therapeutic targets to treat SCI patients.

Public Health Relevance

Patients with spinal cord injury (SCI) suffer from permanent disabilities but have limited treatment and therapeutic options. A major reason for the permanent deficits is the inability of axons in the spinal cord to regenerate through the scar tissue that develops at the injury site. Fibroblasts have been implicated as a major component of this scar tissue, but there have been limited animal studies directly addressing this issue. We will use genetics and pharmacology in animal models to test whether targeting fibroblasts can reduce scarring and promote axon regeneration and functional recovery after SCI.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS081040-02
Application #
8534831
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2012-09-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$322,974
Indirect Cost
$111,880

  Institution

Name
University of Miami School of Medicine
Department
Type
Organized Research Units
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146

  Publications

Hong, Le Thi Anh; Kim, Young-Min; Park, Hee Hwan et al. (2017) An injectable hydrogel enhances tissue repair after spinal cord injury by promoting extracellular matrix remodeling. Nat Commun 8:533
Zhu, Y; Lyapichev, K; Lee, D H et al. (2017) Macrophage Transcriptional Profile Identifies Lipid Catabolic Pathways That Can Be Therapeutically Targeted after Spinal Cord Injury. J Neurosci 37:2362-2376
Funk, Lucy H; Hackett, Amber R; Bunge, Mary Bartlett et al. (2016) Tumor necrosis factor superfamily member APRIL contributes to fibrotic scar formation after spinal cord injury. J Neuroinflammation 13:87
Hackett, Amber R; Lee, Jae K (2016) Understanding the NG2 Glial Scar after Spinal Cord Injury. Front Neurol 7:199
Hackett, Amber R; Lee, Do-Hun; Dawood, Abdul et al. (2016) STAT3 and SOCS3 regulate NG2 cell proliferation and differentiation after contusive spinal cord injury. Neurobiol Dis 89:10-22
Clausen, Bettina Hjelm; Degn, Matilda; Sivasaravanaparan, Mithula et al. (2016) Conditional ablation of myeloid TNF increases lesion volume after experimental stroke in mice, possibly via altered ERK1/2 signaling. Sci Rep 6:29291
Zhu, Y; Soderblom, C; Krishnan, V et al. (2015) Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis 74:114-25
Zhu, Yunjiao; Soderblom, Cynthia; Trojanowsky, Michelle et al. (2015) Fibronectin Matrix Assembly after Spinal Cord Injury. J Neurotrauma 32:1158-67
Soderblom, Cynthia; Lee, Do-Hun; Dawood, Abdul et al. (2015) 3D Imaging of Axons in Transparent Spinal Cords from Rodents and Nonhuman Primates eNeuro 2:
Lee, Do-Hun; Lee, Jae K (2013) Animal models of axon regeneration after spinal cord injury. Neurosci Bull 29:436-44

Showing the most recent 10 out of 11 publications