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Progranulin Function in Spinal Cord Injury and Neuroinflammation

NAPHADE, SWATI B.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1309888495

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
In 2006, null mutations in the progranulin (GRN) gene were identified as a cause of severe neurodegeneration in several familial forms of frontotemporal lobar degeneration. Following this breakthrough discovery, elucidating GRN function in CNS health and disease became one of the topmost priorities in the dementia field. To date, efforts to characterize GRN function in the CNS have primarily focused on rodent models of neurodegeneration and haploinsufficiency that not only have limited sensitivity but are also slow to develop useful phenotypes. To bypass these limitations, we applied the spinal cord injury (SCI) paradigm to address the role of GRN in a well-characterized animal model that is accompanied by a fulminant inflammatory response. Whereas spinal cord sections prepared from non-injured laminectomy control animals contained low basal levels of GRN immunoreactivity in the gray matter, sections from injured animals contained intense immunoreactivity throughout the injury epicenter that peaked 7-14 days post injury. Immunoblot analysis confirmed that GRN protein levels rose after injury. On the basis of polymerase chain reaction analysis, increased protein levels resulted from a ten-fold rise in GRN transcripts. GRN immunoreactivity colocalized with myeloid cell markers CD11b and CD68, indicating that GRN is expressed by activated microglia and macrophages in response to SCI. These data demonstrate that GRN is dramatically induced in myeloid cells after experimental SCI and is positioned both spatially and temporally to influence recovery after injury. We and others have demonstrated that activated macrophages and microglia are the primary cellular sources of GRN expression, however, the role of this extracellularly secreted GRN in response to CNS injury and disease is not known. We propose that GRN plays a pivotal role in modulating the inflammatory response by driving macrophage and microglial polarization. Using in vitro primary macrophage cultures, we demonstrated that while the intact full-length GRN likely induces macrophage differentiation toward the M2 phenotype, an activation state more favorable for CNS recovery, its proteolytically cleaved peptides (granulins) elicit an M1 response, which equates with prolonged, aggravated inflammation and impaired recovery. Therefore, regulating the conversion of GRN to granulins may hold the key to improving anatomical and functional outcomes following pathological insults to the CNS. Since inflammation is at the base of many pathological states in the CNS, we believe that the findings of this study will be broadly applicable to other neurodegenerative disorders and models of CNS injury as well.
JEFF KURET, PhD (Advisor)
CHRISTOPHER PHIEL, PhD (Committee Member)
MARIANO VIAPIANO, PhD (Committee Member)
SANDRA KOSTYK, MD, PhD (Committee Member)
111 p.
Neurobiology; Neurology; Neurosciences
progranulin; spinal cord injury; macrophages; microglia; neuroinflammation; neurodegeneration

Recommended Citations

Citations

  • NAPHADE, S. B. (2011). Progranulin Function in Spinal Cord Injury and Neuroinflammation [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1309888495

    APA Style (7th edition)

  • NAPHADE, SWATI. Progranulin Function in Spinal Cord Injury and Neuroinflammation. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1309888495.

    MLA Style (8th edition)

  • NAPHADE, SWATI. "Progranulin Function in Spinal Cord Injury and Neuroinflammation." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1309888495

    Chicago Manual of Style (17th edition)

osu1309888495
409
© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.