Integrated glycomics and proteomics in aging, Parkinson's disease and cancer
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Parkinson’s disease (PD) is a neurological disorder characterized by the lack of functional dopaminergic neurons in the nigrostriatal pathway in the brain. Current therapeutic strategies for the disease provide temporary symptomatic relief. Gene therapy has the potential to improve dopamine production in Parkinson’s disease patients. Adeno-associated viruses (AAV) are the vectors of choice in gene therapy for PD, due to their well-characterized safety and efficacy profiles, with all primary receptors being glycans. The problem with using AAV in PD gene therapy is that the aged brain is resistant to transduction of the virus, while PD primarily occurs with age. Thus, in Aim 1 we characterize the age-related changes in glycan receptors in the nigrostriatal pathway as a baseline to address current challenges in gene delivery in Parkinson’s disease. To make these measurements from specific regions of tissue, we develop a platform that incorporates on-slide digestion followed by LC-MS/MS for integrated glycomics and proteomics. Further, we apply this to understand aging- and PD-related changes in the human pre-frontal cortex in Aims 2 and 3, to understand normal and pathological aging processes as well as integrate this information with transcriptomics data, to assess risk factors that may contribute to Parkinson’s disease. Finally, we also apply the method to investigate cancer premalignancy and heterogeneity. Our on-slide method, used herein to study aging, Parkinson’s disease and cancer, can be applied to any precious biopsy specimens to enable glycomic and proteomic profiling in diverse diseases, and thus may have a broad impact on biomedical research.
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