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The Orr lab investigates the roles of glial cells and mitochondria in the brain. Our goal is to understand the mechanisms of glial-neuronal communication and mitochondrial signaling in normal and pathophysiological processes. We focus on the effects of receptor signaling in astrocytes and microglia and the production of mitochondrial reactive oxygen species in health and disease.
Glial cells, including astrocytes and microglia, are abundant and critical for many aspects of brain function, including metabolic homeostasis, neuronal communication and responses to injury and disease. Increasing evidence suggests that glial dysfunction is an important factor in most, if not all, disorders of the brain. We are particularly interested in how genes and proteins linked to frontotemporal dementia (FTD) and Alzheimer's disease (AD) impair glial cells and disrupt glial-neuronal interactions that are critical for normal brain function and resilience to disease. Although the underlying causes of these disorders are not clear and no effective treatments are available, new research suggests that glial cells may hold the keys to prevention and effective treatment of these and other neurological disorders.
Most cellular activities that go awry in neurodegenerative disease require mitochondrial signaling. These activities include neural transmission, immune responses and metabolism. Mitochondria in neurons and glial cells likely play key roles in neurodegeneration by regulating how the brain responds to injury. Our lab is currently investigating if and how mitochondrial production of reactive oxygen species contributes to aberrant glial and neuronal responses in experimental models of neurodegenerative disease.
The Orr lab explores glial-neuronal interactions and mitochondrial function using diverse in vitro and in vivo approaches, including chemogenetics, biochemistry, microscopy, behavioral testing, and transgenic mouse models that recapitulate key neuropathological hallmarks of human disease. Findings obtained in experimental models are validated in human samples, such as human cell cultures and postmortem brain tissue. Insights gained from our studies are used to better understand the underlying causes of disease and help develop novel therapeutic interventions targeting key pathogenic cascades. These efforts may lead to the repurposing of known therapeutic agents and the discovery of new strategies to prevent neurological disease.