UC Irvine

Despite significant advances in drug discovery, the development of therapeutics to treat central nervous system (CNS) disease including brain tumors, neurodegenerative diseases, trauma, stroke, and autoimmune diseases, remains a major challenge. Conventional treatments have been revolutionized by the emergence of next generation therapeutics, including biologics, stem cells, and gene therapies. These therapies are characterized by high specificity and better therapeutic efficacies, which have shown great promise to repair and restore lost functions.

The dissertation work presented herein utilizes next generation therapeutics to elucidate the neural mechanisms associated with pathological and healthy states. First, I investigated whether stem cell-derived extracellular vesicles (EVs) can cross the blood-brain barrier (BBB), a dynamic interface that restricts and controls the passage of substances between the peripheral vascular circulation and the CNS. Using the in vitro BBB model under conditions that mimic the healthy and inflamed BBB in vivo, I examined the interaction between EVs and BBB. My results suggest that EVs can cross the BBB under stroke-like conditions in vitro, in effect utilizing the transcellular route of crossing. This work provides insight into the development of nanotherapeutics or diagnostic tools.

The second part of my dissertation focuses on elucidating the role of cytoplasmic polyadenylation element binding protein 3 (CPEB3) ribozyme in learning and memory. I used a gene therapy approach, specifically antisense oligonucleotides (ASOs), to scrutinize the behavioral phenotypes and molecular mechanisms underlying memory consolidation. I demonstrated that the CPEB3 ribozyme plays a role in synaptic plasticity, in which it modulates CPEB3 protein expression. Upon neuronal stimulation or training-induced learning, the CPEB3 ribozyme is shown to facilitate plasticity-related proteins (PRPs) polyadenylation and translation, resulting in upregulation of PRPs at synapses. The regulation of CPEB3 protein and PRPs by CPEB3 ribozyme further leads to a change in long-term memory formation.