Project Details
Description
Neuromyelitis optica (NMO) is a severe, relapsing IgG-mediated autoimmune disease targeting the
central nervous system (CNS), inducing inflammation and preferential demyelination of optic nerve and
spinal cord. Most patients experience severe impairments. IgG autoantibodies specific for the astrocytic
aquaporin-4 (AQP4) water channel are the primary cause of the disease pathophysiology. However,
little is known about the mechanisms driving NMO lesion progression following the binding of IgG to the
astrocyte membrane on entering the CNS. Our proposed project will investigate the potential
contribution of microglia, the resident immune cell of the CNS, to the evolving NMO lesion. We have
developed an informative mouse model of NMO. NMO-IgG is infused intrathecally. Our preliminary
results show significant motor dysfunction, astrocyte activation, and a unique pattern of early microglial
convergence on astrocytes. Prevention of microglial activity suppressed development of motor
dysfunction. In sum, these data clearly indicate astrocyte-microglia communication as an early event
after NMO-IgG enters the CNS.
Aim 1, will investigate the mechanisms underlying astrocyte-microglia crosstalk; Aim 2, will assess the
contribution of microglia to NMO pathogenesis, and Aim 3 will utilize novel genetic tools to manipulate
microglial activity as a potential therapeutic approach to NMO management.
The research we propose represents the first attempt to investigate the specific contribution of microglia
to NMO pathogenesis. The results should clarify the importance of astrocyte-microglia crosstalk and its
underlying mechanisms in NMO. The study will not only improve understanding of neuroimmune
interaction in NMO but will potentially establish that microglia are a pertinent target for NMO therapy.
Status | Active |
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Effective start/end date | 6/1/20 → 4/30/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $461,459.00
- National Institute of Neurological Disorders and Stroke: $461,459.00
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