Immunopeptidomics - Radiotherapy induced changes in phosphoantigenic MHC-I peptides
The adaptive immune response is an essential safeguard against cancer. A critical requirement for T cell recognition is the expression of novel peptides that arise from mutational changes to endogenous protein sequences. These altered sequence peptides, AKA "neoantigens", are presented by major histocompatibility complex class-I (MHC-I) molecules and recognized by CD8+ T cells as non-self, leading to clearance of tumorigenic cells. More recently, it has been shown that in addition to changes in amino acid sequence, posttranslationally modified peptides, notably phosphorylated sequences, can elicit similar T cell responses. Irradiated tumor cells undergo significant alteration of their intracellular signaling pathways, including DNA damage repair pathways and stress pathways, which operate principally through protein phosphorylation. Thus, we hypothesize that generation of novel phosphoantigens may contribute to the ability of radiation to enhance tumor immunogenicity. Radiation is expected to increase the number and diversity of phosphoantigens a hypothesis supported by our preliminary data.
Identifying the roles of altered macroautophagy in neurodegenerative disease
Many lines of evidence indicate that disruption of the lysosome-mediated degradation pathway, autophagy, is a major component of neurodegenerative disease etiology, but it is unclear how it contributes to disease. In Alzheimer's Disease (AD), autophagic dysregulation has been noted in patient samples and large scale sequencing efforts have identified multiple genetic variants in components of the autophagic machinery in familial disease. In experimental model systems, genetic modulation of autophagy exacerbates the toxicity of phospho-tau and amyloidosis. Similar evidence suggests roles for autophagy in the pathogenesis of a broad array of neurodegenerative diseases such as Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, the synucleinopathies, and Huntington’s disease. How dysregulation of a fundamental, widely active homeostatic pathway leads to diseases with discrete neuropathological and neurological changes remains unclear.
In collaboration with Ai Yamamoto at Columbia University, we are profiling the protein contents of highly purified autophagosomes from mouse brains. By identifying differences in autophagic cargoes in mouse models of genetic disease, we hope to understand how changes in autophagy lead to the neuronal dysfunction and death that give rise to disease.