Tuesday, January 28, 2025
1/28/2025
ABSTRACT There is a high incidence of neurological disorders (HAND) in middle-aged people living with HIV infection (PLWH). To date, the molecular causes for diverse array of HAND remain poorly understood, and specific pharmacological interventions to manage HAND remain elusive. The working hypothesis for this R21 is “that the reactive glycolytic byproduct methylglyoxal (MG) is triggering the multitude of early-onset neurological disorders by exerting varying actions of different cell types in the brain”. The aims are (1) define pathobiological trajectory of early-onset neurological disorders in relation to MG, Glo-1, microvascular leakage, and inflammation in HIV-1 infected Hu-mice with and with anti-retroviral treatment, and (2) show that lowering MG with novel, cell- penetrant arginine-rich cyclic peptides will blunt neurological disorders in HIV-infected Hu-mice with and without anti-retroviral treatment. Data generated from this R21 will establish for the first time a link between the elevated levels of the glycolysis byproduct MG, microvascular leakage, impaired synaptic transmission, and neurological disorders, in our clinically relevant HIV-1 infected Hu-mice model. Preliminary structure-activity relationship studies will also provide novel insights into the use of arginine-rich cyclic peptides to scavenge MG and attenuate these early-onset HAND.
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