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Keypoint Newsletter: December 2024
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Research in the Brown lab focuses on how breach of the blood-brain-barrier by viral pathogens like the human immunodeficiency virus type 1 (HIV-1), alters brain homeostasis. Central to this research is acquiring a detailed mechanistic understanding of the pathways leading to sustained neuroinflammation. HIV-1 robustly infects microglia and macrophages, but not neurons and to a lesser extent, astrocytes. In the absence of antiviral treatment, in 20% of infected persons, severe encephalitis, memory impairment and debilitating gait abnormalities can occur. The use of small molecule inhibitors, which block discrete steps of the viral life cycle, has greatly reduced severe neurocognitive impairment. However, in a large fraction of infected persons, functional deficits remain. The Brown lab is testing the hypothesis that ongoing low-level replication that persists in tissues including the brain, drives chronic activation of proinflammatory signaling. The ultimate aim of the research is to apply the knowledge gained to develop new and better treatments to ameliorate HIV-associated cognitive comorbidities. In order to identify the molecular mechanisms of neuroinflammation, reductionist strategies with physiologically relevant primary cell culture, and cutting-edge tools in neuroscience are used. At the same time humanized rodent models are employed to test potential hypotheses and/or validate findings in a living system that approximates, or models an aspect of brain disease, and possibly behavioral phenotypes seen in the context of human neuropathology and impairment. For the last several years, the Brown lab has sought and made progress in understanding the role of the multifunctional protein, osteopontin (OPN), which is encoded by the SPP1 gene, in the nervous system. OPN has long been described in neurodegenerative disorders like Alzheimer’s and Parkinson’s disease, multiple sclerosis (MS), and fronto-tempro dementia as a putative biomarker. However, except for MS, there is a profound lack of insight into OPN’s mechanistic function (s) in the brain. Exciting recent findings from the Brown laboratory and their collaborators which used micro-PET-imaging on HIV-infected humanized mice, suggest that OPN is a master regulator of neuroinflammation.
Research Area(s):
NeurobiologyResearch Keywords:
Mentor: Beverly M. Emerson, PhD
Dec 20, 2024 by Shannon Weiman
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