The primary interests of this workgroup focus on the pathogenesis and treatment of chronic neurodegenerative diseases, many of which involve alterations in neurotransmitter receptor systems subserving normal CNS function as a result of derangements in peripheral organ function. For example, hepatic encephalopathy (HE) is a neuropsychiatric syndrome accompanying acute or chronic liver failure. It is characterized by personality changes, sleep inversion, generalized cognitive slowing, incoordination and ataxia leading to coma. We are investigating the role that endogenous benzodiazepine receptor ligands, neurosteroids, and ammonia play in the pathogenesis of this syndrome and developing pharmacological interventions to deal with these changes. Another chronic neurodegenerative disorder under investigation is AIDS dementia complex. We are presently characterizing many of the basic immunological and neurological pathologies of a murine model of retrovirus-induced cognitive deficits. These models are being used to investigate the role of excitotoxins, cytokines and autoimmune factors in the pathogenesis of the behavioral and neurochemical abnormalities associated with retroviral infections in these mice, and treating them with cytokine synthesis inhibitors, anti-inflammatories, or glutamate receptor antagonists, then noting their efficacy. In addition to investigations of pharmacological techniques for limiting neurodegeneration and cognitive loss, we are phasing in behavioral characterizations of knockout and transgenic mouse models of disease, as well as development of modalities for imaging transplanted pancreatic islet cells and other imaging techniques.
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