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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2020)

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.

    Cover page: New therapeutic approaches to study brain mechanisms: Utilizing stem cells and gene therapy to investigate brain diseases, learning, and memory
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2024)
    Osteosarcoma (OS) is a primary malignant bone tumor with high metastasis. Poor prognosis highlights a clinical need for novel therapeutic strategies. Exosomes, also known as extracellular vesicles, have been identified as essential players in the modulation of cancer. Recent studies have suggested that OS-derived exosomes can drive pro-tumorigenic or anti-tumorigenic phenotypes by transferring specific cargos, including proteins, nucleic acids, and metabolites, to neighboring cells, significantly impacting the regulation of cellular processes. This review discusses the advancement of exosomes and their cargos in OS. We examine how these exosomes contribute to the modulation of cellular phenotypes associated with tumor progression and metastasis. Furthermore, we explore the potential of exosomes as valuable biomarkers for diagnostics and prognostic purposes and their role in shaping innovative therapeutic strategies in OS treatment development.
      Cover page: Exploring the Impact of Exosomal Cargos on Osteosarcoma Progression: Insights into Therapeutic Potential
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2022)
      Loss-of-function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis, and poor therapeutic outcome in several cancers, including osteosarcoma. However, the mechanism(s) through which RB1 loss worsens clinical outcome remains understudied. Ubiquitin-like with PHD and Ring Finger domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F signaling pathway that is overexpressed in various cancers. Here, we determined the role and regulatory mechanisms of UHRF1 in rendering osteosarcoma cells more aggressive. Higher UHRF1 expression correlated with malignancy in osteosarcoma cell lines, clinical samples, and genetically engineered mouse models. Gain- and loss-of-function assays revealed that UHRF1 has cell-intrinsic and extrinsic functions promoting cell proliferation, migration, invasion, angiogenesis, and metastasis. UHRF1 overexpression induced angiogenesis by suppressing AMPK activation and Semaphorin 3E (SEMA3E) expression. Further, UHRF1-mediated migration and metastasis resulted, at least in part, through altered expression of extracellular vesicles and their cargo, including urokinase-type plasminogen activator (uPA). Novel osteosarcoma genetically engineered mouse models confirmed that knocking out Uhrf1 considerably decreased metastasis and reversed the poorer survival associated with Rb1 loss. This presents a new mechanistic insight into RB1 loss-associated poor prognosis and novel oncogenic roles of UHRF1 in the regulation of angiogenesis and exosome secretion, both critical for osteosarcoma metastasis. This provides substantial support for targeting UHRF1 or its downstream effectors as novel therapeutic options to improve current treatment for osteosarcoma.
        Cover page: UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2016)
        The delivery of therapeutics to the central nervous system (CNS) remains a major challenge in part due to the presence of the blood-brain barrier (BBB). Recently, cell-derived vesicles, particularly exosomes, have emerged as an attractive vehicle for targeting drugs to the brain, but whether or how they cross the BBB remains unclear. Here, we investigated the interactions between exosomes and brain microvascular endothelial cells (BMECs) in vitro under conditions that mimic the healthy and inflamed BBB in vivo. Transwell assays revealed that luciferase-carrying exosomes can cross a BMEC monolayer under stroke-like, inflamed conditions (TNF-α activated) but not under normal conditions. Confocal microscopy showed that exosomes are internalized by BMECs through endocytosis, co-localize with endosomes, in effect primarily utilizing the transcellular route of crossing. Together, these results indicate that cell-derived exosomes can cross the BBB model under stroke-like conditions in vitro. This study encourages further development of engineered exosomes as drug delivery vehicles or tracking tools for treating or monitoring neurological diseases.
          Cover page: Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro.Creative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2017)
          Despite decades of effort, little progress has been made to improve the treatment of cancer metastases. To leverage the central role of the mechanoenvironment in cancer metastasis, we present a mechanoresponsive cell system (MRCS) to selectively identify and treat cancer metastases by targeting the specific biophysical cues in the tumor niche in vivo. Our MRCS uses mechanosensitive promoter-driven mesenchymal stem cell (MSC)-based vectors, which selectively home to and target cancer metastases in response to specific mechanical cues to deliver therapeutics to effectively kill cancer cells, as demonstrated in a metastatic breast cancer mouse model. Our data suggest a strong correlation between collagen cross-linking and increased tissue stiffness at the metastatic sites, where our MRCS is specifically activated by the specific cancer-associated mechano-cues. MRCS has markedly reduced deleterious effects compared to MSCs constitutively expressing therapeutics. MRCS indicates that biophysical cues, specifically matrix stiffness, are appealing targets for cancer treatment due to their long persistence in the body (measured in years), making them refractory to the development of resistance to treatment. Our MRCS can serve as a platform for future diagnostics and therapies targeting aberrant tissue stiffness in conditions such as cancer and fibrotic diseases, and it should help to elucidate mechanobiology and reveal what cells "feel" in the microenvironment in vivo.
            Cover page: Mechanoresponsive stem cells to target cancer metastases through biophysical cues.Creative Commons 'BY' version 4.0 license
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