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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2010)

Recent advances in micro/nano- technologies have shown high potentials in the field of quantitative biology, biomedical science, and analytical chemistry. However, micro/nano fluidics still requires multi-layered structures, complex plumbing/tubing, and external equipments for large-scale applications and nanotechnology-based sensors demand high cost. Interestingly, nature has much simpler and more effective solutions. The goal of this dissertation is to develop novel microfluidic platforms and nanobiosensors inspired by biological systems.

In this dissertation, I report the development of a biologically inspired bidirectional fluidic diode motivated by the xylem pores, which allows designing a functional large-scale microfluidic circuit and autonomous fluidic controls without any delegate efforts on fluid regulation. The biologically inspired bidirectional fluidic diode requires only a single-layered structure and a single pressure source to regulate flow in both directions through the entire platform. The operational conditions are precisely estimated based on the fully developed analytical model, which considers the hysteresis of contact angles and effects of fabrication limitations. To demonstrate its many possible applications, I show large-scale, spontaneous droplet-patterning and colonized cell-patterning programmed with the uni- and bi-directional fluidic diodes in the microfludic platform. In addition, inspired by target recognition in nature, an aptamer-based nanoplasmonic sensor, `aptasensor' is presented by detecting a coagulation protein, human α-thrombin. Also, I present an aptasensor targeting vascular endothelial growth factor-165 (VEGF165), a predominant and effective cancer biomarker for the diagnostics of various solid cancers. The integration of an aptasensor into a microfluidic platform is demonstrated by applying the VEGF165 aptasensor to detect secreted VEGF165 from breast cancer cells cultured in a microfluidic platform.

I envision that elucidation of mechanisms underlying in biological systems will inspire to create new technologies for the application to precision biology, biotechnology, and medicine. Furthermore, the developed biologically inspired engineering will provide physical insights, analytical models, and useful tools for the better understanding of biological systems.

    Cover page: Biologically-inspired Microfluidic Platforms and Aptamer-based Nanobiosensors
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2024)
    Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aβ)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.
      Cover page: Neurotoxic Microglial Activation via IFNγ‐Induced Nrf2 Reduction Exacerbating Alzheimer's Disease
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2022)
      The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in greater release of Ca2+ from the endoplasmic reticulum stores, which triggers sustained Ca2+ influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca2+ using a P2Y12 receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca2+ response to purinergic signals, suggesting a window of Ca2+ signaling for optimal microglial motility.
        Cover page: TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2020)
        The discovery of TREM2 as a myeloid-specific Alzheimer's disease (AD) risk gene has accelerated research into the role of microglia in AD. While TREM2 mouse models have provided critical insight, the normal and disease-associated functions of TREM2 in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified TREM2-knockout induced pluripotent stem cell (iPSC) lines. By combining transcriptomic and functional analyses with a chimeric AD mouse model, we find that TREM2 deletion reduces microglial survival, impairs phagocytosis of key substrates including APOE, and inhibits SDF-1α/CXCR4-mediated chemotaxis, culminating in an impaired response to beta-amyloid plaques in vivo. Single-cell sequencing of xenotransplanted human microglia further highlights a loss of disease-associated microglial (DAM) responses in human TREM2 knockout microglia that we validate by flow cytometry and immunohistochemistry. Taken together, these studies reveal both conserved and novel aspects of human TREM2 biology that likely play critical roles in the development and progression of AD.
          Cover page: Gene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease
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