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Neuro-Immune Interactions in Parkinson's Disease

Parkinson's disease is a prevalent neurodegenerative disorder wherein recent evidence suggests pathogenesis may be medicated by inflammatory processes. The molecular architecture of the disease remains to be fully elucidated. We hypothesize that Parkinson's disease is initiated by an autoimmune process involving alpha-synuclein-specific T cell activation by gut microbiome dysbiosis, followed by neuro-immune interactions that establish the disease in the brain. We integrate neuroimmunology, single-cell genomics, mouse models, and microbiome approaches to examine whether T cell-mediated autoimmunity initiates the neurodegneration process in Parkinson's disease, and if these early immunological processes converge on classic archetypes of neurodegeneration. This work will produce an unprecedented map (the "interactome") of the neuro-immune interactions that are perturbed in Parkinson's disease, identifying rational targets for clinical trials and paving the way for the development of new treatments.

Supporting Grants

  • Aligning Science Across Parkinson's ASAP-000529 (PI Hafler) Tracing the Origin and Progression of Parkinson's Disease through the Neuro-Immune Interactome
  • Aligning Science Across Parkinson's ASAP-000580 (PI De Camilli) Impaired integration of organelle function in Parkinson's disease

Sex Difference in Alzheimer's Disease

Alzheimer's disease is the most common neurodegenerative disease, characterized by progressive cognitive decline and dementia and coupled with accumulation of brain amyloid-ß and tau aggregates. there is no effective treatment available to slow or halt the fatal progression of Alzheimer's disease. The risk and severity of Alzheimer's disease is more pronounced in women than in men, but the mechanisms of sex variance are still poorly understood. To define the molecular architecture of sex-dependent responses, we profile the gene expression in hundreds of thousands of male and female brain cells with and without the Alzheimer's disease, and relate these profiles to genome variation of Alzheimer's risk. The biological significance and mechanism of the most prominent sex-specific genes and therapeutic interventions will be studied in mouse models of Alzheimer's disease.

Supporting Grants

  • R56AG074015 (PI Strittmatter/Zhang/Rothlin/Ghosh/Zhao) Sex-Specific Single Cell Expression Profiles, Genetic Risk and Drug Responsiveness in Alzheimer's Disease
  • Yale Alzheimer's Disease Research Center Research Scholar Award (PI Zhang)
  • Women's Health Research at Yale Pilot Project Award (PI Zhang)
  • Yale Alzheimer's Disease Research Center Pilot Project Award (PI Zhang)

Immune Network Dysregulation of the Central Nervous System with HIV Persistence and Opioid Abuse

HIV persists within the central nervous system, despite successful suppression of viral replication with antiretroviral therapy, leading to incomplete viral eradication, as well as HIV-associated neurocognitive disorder that is further exaggerated by opioid abuse. Yet, the underlying molecular and cellular mechanisms remain the mystery. We employ state-of-the-art and novel methodologies in neuroscience, immunobiology, and computational biology to dissect the dysregulated immune network in the central nervous system of individuals with HIV infection with and without opioid exposure at the single-cell level and the cell-type-specific response to opioids in the context of HIV. This study will open up new vistas in the important area of HIV persistence and neuroinflammation in the central nervous system, and may provide additional, foundational knowledge for the development of future therapeutics to treat HIV in individuals with and without opioid use disorder.

Supporting Grants

  • DP2DA056169 (PI Zhang) Immune Network Dysregulation of the Central Nervous System with HIV Persistence and Opioid Abuse
  • UM1DA051410 (PI Spudich/Kluger/Gerstein) The Y-SCORCH Data Generation Center at Yale for Single-Cell Opioid Responses in the Context of HIV