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Xiqun Chen, M.D.


Available: 10/01/21, Expires: 10/30/24

Although Parkinson's disease (PD) and cancer are defined pathologically by neuron loss and cell overgrowth, respectively, they have been linked to some of the same gene alterations. LRRK2 mutations, the most common cause of autosomal dominant late-onset PD, are associated with an increased risk of cancer. Mutations of Parkin, a potent tumor suppressor gene, are the most common cause of autosomal recessive early-onset PD. While advances in cancer immunology are revolutionizing the treatment of cancer, there is a growing appreciation of the role of the immune system in PD. Previous and our preliminary studies support that PD and cancer-related LRRK2 and Parkin alterations can lead to dysregulated immune responses. The overall goal of the proposed study is to investigate whether and how the genetic connections between PD and cancer alter immune tolerance to dopaminergic neurons and contribute to dopaminergic neurodegeneration at the cellular, tissue, and systemic levels and in patient samples. Two specific aims will be pursued to determine whether 1) LRRK2 and Parkin alterations reprogram immune responses against dopaminergic neurons; 2) cancer-educated immune system alters dopaminergic-specific autoimmunity. Backed by exceptional expertise and resources from cancer research and neuroscience, two major disciplines that rarely crosstalk, the proposed work strikes a balance between high risk and high return to address issues relevant to both "Biology of PD-associated Genes" and "Neuro-immune Interactions". Its findings are expected to advance our understanding of the molecular events in the immune system leading to tumorigenesis in dividing cells and neurodegeneration as part of the systemic disorders in response to the same genetic triggers. These molecular insights would open new avenues for prevention and therapies for PD by offering a range of therapeutic targets, as well as the possibility that immune approaches developed in cancer will find applications in PD.

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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.