Inflammation, a function of the innate immune system, occurs in both acute and chronic neurodegenerative conditions. However, we do not know how immune function is mechanistically related to neuronal maintenance such as degeneration and regeneration. Sarm1 is a promising candidate in defining this mechanism. Sarm1 is the central mediator of axon degeneration. Recently, Sarm1 was also found to be a factor of the innate immune system. Yet, the function of Sarm1 in the immune response, and the effect of the immune response on neuronal degeneration, remain unknown. This study will contribute to our mechanistic understanding of the relationship between neuroimmune recruitment and neurodegeneration by elucidating the role of Sarm1, through the following aims:
Aim 1 : Define the Drosophila innate immune response to axon injury. Hemocytes, the innate immune cells of Drosophila, interact with injured axons. But, the function of this interaction is unclear. I will correlate the course of hemocyte recruitment with known events in axon degeneration and regeneration to identify a role for the innate immune system during injury. I will also assess what defects in axonal injury and repair occur in the absence of hemocytes.
Aim 2 : Determine the role of Sarm1 in mediating neuroimmune response. I will determine if Sarm1 is necessary and sufficient for hemocyte recruitment. I will then interrogate the molecular mechanism of Sarm1 mediated immune recruitment by manipulating the enzymatic activity of Sarm1, which has recently been shown to be required for immune response in plants.
Aim 3 : Identify innate immune messengers and pathways activated by axonal injury. To determine the mechanism mediating immune recruitment to injured neurons, I will identify cytokines and downstream signaling pathways required for neuroimmune interaction after injury. Successful completion of this proposal will bridge gaps in knowledge relating to the initiation of neuroimmune recruitment during axon degeneration.
Inflammation, a function of the innate immune system, occurs as a result of both acute and chronic neurodegenerative conditions. We do not currently know the mechanism linking the innate immune response and neuronal degenerative processes. This study will explore the role of Sarm1, a gene of central importance to axonal degeneration and recently implicated as a factor of the innate immune system.
