Preventing and Reducing HAND by Using New BDNF Nanoprobes

DESCRIPTION provided by applicant Human immunodeficiency virus HIV associated neurocognitive disorder HAND represents a major chronic health problem in the US and abroad MRI studies of HAND consistently show a decrease in the size of the hippocampus and other brain structures associated with learning and memory Advances in treatment of HAND have been made by administering brain derived neurotrophic factor BDNF directly to the CNS or by using drugs that can increase BDNF indirectly BDNF promotes neuronal plasticity and restores brain functions However BDNF cannot cross an intact blood brain barrier BBB and is unstable in the blood or when delivered orally The goal of this effort is to produce non toxic BDNF nanoparticles and to test the hypothesis that these nanoprobes bypass the BBB intranasally target BDNF receptor rich brain regions and prevent or reverse neurotoxic effects of HIV transactivator of transcription tat protein in a mouse model relevant to HAND the GT tg bigenic mouse induced with doxycycline to overexpress tat protein To accomplish these goals we will design a two part nanoprobe andlt nanometers A nanocarrier will be constructed out of clathrin a naturally occurring protein the body uses for transporting molecules into cells The second component will be a BDNF protein drug BDNF will be attached to polyethylene glycol PEG molecules coating the carrier A series of studies will ascertain the affinity specificity ad functionality of the nanoprobes in vivo We plan to demonstrate the feasibility of this novel nanotechnology to prevent and treat tat neurotoxicity associated with HAND If this research project is successful it will provide new noninvasive nanotechnology tools for prevention and treatment of neurotoxicity that may be useful for treating HAND The new nanotechnology may be able to enhance neuronal plasticity and restore brain functions more quickly and completely than existing treatment methods while using much lower therapeutic drug doses and causing fewer side effects The development of a stable targeted molecular nanoprobe may also provide a major new tool for research of molecular abnormalities in HAND and co morbid disorders This novel nanotechnology may serve as the basis for a next generation drug delivery system that can specifically target relevant brain systems and also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease PUBLIC HEALTH RELEVANCE The development of new targeted noninvasive nanotechnologies for prevention and treatment of HAND will provide a major new tool which would be able to enhance neuronal plasticity and restore brain functions quicker and better than existing treatment methods and with less side effects This new nanotechnology may serve as a new drug delivery system that can specifically target relevant brain systems and also may have utility as an imaging agent to enhance diagnosis