ABSTRACT
Globoid Cell Leukodystrophy (GLD) is a demyelinating central nervous system (CNS) disease that results in
death in 99% of children before the age of 5 years old. Loss of function mutation in galactocerebrosidase in GLD
leads to a toxic build-up of the lipid psychosine, which is currently thought to underlie the development of this
disease. The rapid progression of behavioral and cognitive deficits present in GLD is devastating for both patients
and families, however current treatments have limited success at modulating these symptoms. Therefore, it is
critical to further understand the complex cellular changes associated with the pathology of this disease to
develop successful therapies for these patients. Our lab has recently identified a novel role for CD8+ T cells in
the pathology of GLD, however the mechanism underlying the recruitment and activation of these CD8+ T-cells
is unknown. It is known that microgliosis is a prominent feature of GLD neuropathology and our preliminary data
indicate that activated CD68+ microglia are anatomically clustered with CD8+ T-cells in demyelinated lesions in
GLD. We also find that microglia upregulate major histocompatibility complex class I (MHC I) when exposed to
psychosine. Together, these findings indicate that microglia are a plausible antigen presenting cell type
contributing to CD8+ T-cell activation and neuropathology in GLD. We hypothesize that microglial MHC I
expression contributes CD8+ T-cell activation in GLD. Accordingly, in this proposal, we will define and test
the role of microglial MHC I on GLD neuropathology and CD8+ T-cells activation. In Aim 1, we will define the
temporal and anatomical expression patterns of microglial MHC I expression in a GLD mouse model over the
time course of disease. We will also use imaging mass cytometry to corroborate these findings using human
GLD neurospecimens to translate our findings. In Aim 2, we will determine the role of microglial MHC I function
to neuropathology and CD8+ T cell responses in twitcher mice using microglial cell-specific MHC I knockout
mice in the GLD mouse model to investigate effects on disease course, neuropathology and CD8+ T-cell
responses. We will also functionally examine the capability of psychosine to direct microglial MHC I antigen
presentation and CD8+ T-cell activation. The long-term goal of this project is to understand the novel role of
microglial antigen presentation in GLD neuropathology. The expected impact of this project may be a shift in our
thinking on the nature of demyelination in this untreatable disease and the role of microglia in neuropathology.
The training goals of this application will provide both skills and training in neuroimmunology and to enhance
clinical, and professional goals directed toward my future as a physician scientist. Toward these goals, this highly
translational project will take advantage of a strong intellectual environment and unique opportunities available
at UConn School of Medicine and in the sponsor's lab. Collectively, the expected outcomes of this proposal will
foster and support my career aspirations to achieve training in neurological and immunological interactions and
to contribute to the field of neurological disease.