Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY Delivering molecules across the blood-brain barrier (BBB) represents a major challenge in treating mental disorders and central nervous system (CNS) disorders. Many therapeutic agents that have the potential to treat these disorders have difficulty entering the brain due to the presence of the BBB. In this project, we are responding to the NIH PAR-22-031 that calls for development of delivery systems that can target drugs to the brain. We have recently developed BBB modulators (BBBMs) that significantly increase in vivo brain delivery of small-to-large drug molecules including therapeutic peptides and proteins. Recently, BBBMs (i.e., HAVN1 and DWI peptides) have been shown to selectively modulate the BBB over the peripheral vasculatures in the in vitro and in vivo systems. Our hypothesis is that these BBBMs enhance brain delivery of therapeutic proteins by modulating cadherin-mediated cell-cell adhesion in the paracellular pathway of the BBB. The overall goal of this project is aimed at developing and optimizing the next generation of BBBMs as a novel and non-invasive delivery system to target drugs to the brain. BBBMs transiently increase the porosity of the BBB paracellular pathways to allow drugs to enter the brain from the bloodstream. To accomplish the overall goal, we will pursue the following Specific Aims. First, a combination of virtual screening and 3D in vitro models of the BBB vs. peripheral vasculatures will be used to optimize modulatory activity and selectivity of the next generation of BBBMs from VE-cadherin. Second, DMPK profiles, toxicity, and selectivity of BBBMs will be evaluated using animal models. Toxicity of BBBMs in various organs will be determined. Third, the biological effects of BBBMs-facilitated brain delivery of FL-BDNF and BDNF peptides will be evaluated in mouse models of both sporadic and familial Alzheimer's disease (AD). The biological effects of FL-BDNF and BDNF peptides in the brain will be assessed by determining TrkB signaling, synaptic activity, AD neuropathology, and learning and memory. If successful, this project will have impacts on (a) reversing neurodegeneration, (b) improving diagnosis and treatment of brain diseases and injuries, (c) expanding our understanding of how the brain works at both the cellular and molecular levels, and (d) designing new tools for monitoring brain function in vivo.
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