A5085471615- RNA Interference and Gene Delivery
- Barrier Structure and Function Studies
- Neuroinflammation and Neurodegeneration Mechanisms
- Advanced biosensing and bioanalysis techniques
- Neurogenesis and neuroplasticity mechanisms
- DNA and Nucleic Acid Chemistry
- Neurological Disease Mechanisms and Treatments
- Immune cells in cancer
- Cell Adhesion Molecules Research
- Ion Transport and Channel Regulation
- Mitochondrial Function and Pathology
- Drug Transport and Resistance Mechanisms
- Caveolin-1 and cellular processes
- Nanoparticle-Based Drug Delivery
- 3D Printing in Biomedical Research
- Microfluidic and Bio-sensing Technologies
- Anesthesia and Neurotoxicity Research
- MicroRNA in disease regulation
- Pluripotent Stem Cells Research
- Innovative Microfluidic and Catalytic Techniques Innovation
- CRISPR and Genetic Engineering
- Cancer, Lipids, and Metabolism
- Lipid Membrane Structure and Behavior
- Osteoarthritis Treatment and Mechanisms
Vanderbilt University
2020-2025
Emulate (United States)
2022
Biogen (United States)
2021
Abstract Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation astrocytes to reactive states can be protective or harmful BBB Here, using a human induced pluripotent stem cell (iPSC)-derived co-culture model, we show tumor necrosis factor (TNF) transitions an inflammatory state causes dysfunction through activation STAT3 and increased expression SERPINA3 , which encodes alpha 1-antichymotrypsin (α1ACT). To...
Species differences in brain and blood-brain barrier (BBB) biology hamper the translation of findings from animal models to humans, impeding development therapeutics for diseases. Here, we present a human organotypic microphysiological system (MPS) that includes endothelial-like cells, pericytes, glia, cortical neurons maintains BBB permeability at vivo relevant levels. This Brain-Chip engineered recapitulate critical aspects complex interactions mediate neuroinflammation demonstrates...
Abstract CRISPR-Cas systems have emerged as a powerful tool to generate genetic models for studying normal and diseased central nervous system (CNS). Targeted gene disruption at specific loci has been demonstrated successfully in non-dividing neurons. Despite its simplicity, high specificity low cost, the efficiency of CRISPR-mediated knockout vivo can be substantially impacted by many parameters. Here, we used CRISPR-Cas9 disrupt neuronal-specific gene, NeuN, optimized key parameters...
Abstract Osteoarthritis (OA) and rheumatoid arthritis (RA) are joint diseases that associated with pain lost quality of life. No disease modifying OA drugs currently available. RA treatments better established but not always effective can cause immune suppression. Here, an MMP13-selective siRNA conjugate was developed that, when delivered intravenously, docks onto endogenous albumin promotes preferential accumulation in articular cartilage synovia joints. MMP13 expression diminished upon...
Barriers of the central nervous system (CNS), such as blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSFB), regulate two-way exchange material between blood CNS. These barriers pose a considerable challenge for efficacious delivery intravenously administered therapies into CNS, motivating exploration their function ways to modulate properties. While BBB BCSFB can become dysfunctional in patients with chronic CNS diseases, few studies have focused on strategies targeting these...
Osteoarthritis and rheumatoid arthritis are debilitating joint diseases marked by pain, inflammation cartilage destruction. Current osteoarthritis treatments only relieve symptoms, while therapies can cause immune suppression provide variable efficacy. Here we developed an optimized small interfering RNA targeting matrix metalloproteinase 13 for preferential delivery to arthritic joints. Chemical modifications in a stabilizing 'zipper' pattern improved resistance degradation, two independent...
Short-interfering RNA (siRNA) has gained significant interest for treatment of neurological diseases by providing the capacity to achieve sustained inhibition nearly any gene target. Yet, efficacious drug delivery throughout deep brain structures CNS remains a considerable hurdle intrathecally administered therapeutics. We herein describe an albumin-binding lipid-siRNA conjugate that transports along meningeal and perivascular CSF pathways, leading broad dispersion parenchyma. provide...
Abstract In the body, capillary beds fulfill metabolic needs of cells by acting as sites diffusive transport for vital gasses and nutrients. artificial tissues, replicating scale complexity capillaries has proved challenging, especially in a three-dimensional context. order to better develop thick it will be necessary recreate both form function capillaries. Here we demonstrate top–down method patterning hydrogels using sacrificial templates formed from thermoresponsive microfibers whose...
Abstract Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function in brain microvascular endothelial cells (BMECs). Transformation astrocytes to a reactive state response injury and disease can be protective or harmful BBB function, but underlying mechanisms for these effects remain mostly unclear. Using human induced pluripotent stem cell (iPSC)-derived coculture model BMEC-like astrocytes, we found tumor necrosis factor alpha (TNFα)...
Abstract Triple negative breast cancers (TNBCs) are aggressive malignancies with a high rate of recurrence even after neoadjuvant chemotherapy (NAC) and resection. Nearly 50% NAC-treated TNBC patients harboring residual disease display mutations in the phosphatidyl inositol-3 kinase/mechanistic target rapamycin (PI3K/mTOR) pathway, correlating PI3K/mTOR chemoresistance. The protein kinase mTOR functions within two distinct complexes—mTORC1 mTORC2. Inhibition mTORC1 is ineffective TNBCs....
siRNA therapeutics have considerable potential as molecularly-targeted in malignant disease, but identification of effective delivery strategies that mediate rapid intracellular while minimizing toxicity has been challenging. Our group recently developed and optimized an conjugate platform termed "siRNA-L
SUMMARY Species differences in the brain and blood-brain barrier (BBB) biology hamper translation from animal models to humans impede development of specific therapeutics for diseases. Here we present a human Brain-Chip engineered recapitulate critical aspects complex cell-cell interactions that mediate neuroinflammation development. Our organotypic microphysiological system (MPS) includes endothelial-like cells, pericytes, glia, cortical neurons maintains BBB permeability at vivo relevant...
Abstract Brain endothelial cells (BECs) play an important role in maintaining central nervous system (CNS) homeostasis through blood-brain barrier (BBB) functions. BECs express low baseline levels of adhesion receptors, which limits entry leukocytes. However, the molecular mediators governing this phenotype remain mostly unclear. Here, we explored how infiltration immune across BBB is influenced by scaffold protein IQ motif containing GTPase activating 2 (IQGAP2). In mice and zebrafish,...
Abstract Short interfering RNAs (siRNAs) are potent nucleic acid-based drugs designed to target disease driving genes that may otherwise be undruggable with small molecules. However, the potential of administering therapeutic siRNA in vivo is limited by poor pharmacokinetic properties, including rapid renal clearance and nuclease degradation. Nanocarriers have traditionally been explored as means overcome these challenges, but they intrinsic downsides such dose-limiting toxicity synthetic...