Wednesday, January 15, 2025
1/15/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).