Grants and Contracts Details
Across a wide variety of spinal cord injuries the immune response plays an important role in both the progression of pathology and the potential for regeneration. CNS macrophages, derived from monocytes and endogenous microglia, have the potential to contribute to both repair and pathology. More specifically differences in macrophage phenotypes, classically activated phenotype (M1) or alternatively activated phenotype (M2), result in divergent roles in the response to injury. M1 phenotype is associated with greater cell loss and a greater progression in pathology, whereas it is believed that an M2 phenotype promotes cell protection, regeneration, and plasticity. Unfortunately, after injury the environment drives macrophages toward an M1 phenotype. Therefore driving and sustaining an M2 phenotype would involve either changing the environment or the way cells respond to the environment. Focusing on the later approach, we have developed such a way; specifically transplanting genetically engineered macrophages and utilizing the M2 associated triggering receptor expressed on myeloid cells 2 (TREM2). We have preliminary data showing that the transplanted primary macrophages transduced ex-vivo to over-express TREM2 retain an M2 phenotype in injured spinal cord. While this technique shows promise as a potential therapy, it has limitations. Unfortunately, due to the variability in transduction efficiency and the stability of isolated cells, this approach is not ideal. The goal of this proposal is to develop a better way to switch phenotypes using TREM2 by targeting a microglia / macrophage specific promoter in an adenovirus associated viral vector. This will give us the ability to directly target microglia / macrophages in-vivo. Specifically this proposal will focus on using qPCR in a clinically relevant spinal cord contusion injury model to confirm the expression of the microglia / macrophage specific promoter is maintained in endogenous cells post-injury. Further, using both qPCR and immuno-staining we propose to characterize in-vitro the level of expression of TREM2 and to confirm a shift toward an M2 phonotype. This proposal will also entail working with the university’s viral production core to optimize both the viral vector design and delivery. Completion of the proposed experiments will yield a powerful tool in analyzing the role of M2 phenotype macrophages in the dynamics of progression and repair in spinal cord injury. This shift to an M2 response also corresponds to the ability to limit the M1 response, which has been shown to lead to tissue sparing. Further, this could lead to a clinical therapy relevant to the broad spectrum of injuries in which microglia / macrophages are involved. With this proposed project we hope to create an immune response that is conducive to both neuroprotection and regeneration and share Wings for Life’s aims to stop or limit the death of the neuron and the glial and to achieve regeneration of the injured nerve fibres by promoting the ability for regeneration or diminution of the inhibitory signal.
|Effective start/end date
|7/1/13 → 6/30/15
- Wings for Life Spinal Cord Research Foundation: $23,884.00
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