A5009178264- Cancer, Stress, Anesthesia, and Immune Response
- Brain Metastases and Treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- Nanoplatforms for cancer theranostics
- Curcumin's Biomedical Applications
- Single-cell and spatial transcriptomics
- Extracellular vesicles in disease
- Alzheimer's disease research and treatments
- CRISPR and Genetic Engineering
- Immune cells in cancer
- Computational Drug Discovery Methods
- Circular RNAs in diseases
- IL-33, ST2, and ILC Pathways
- Reproductive System and Pregnancy
- Glutathione Transferases and Polymorphisms
- Genomics, phytochemicals, and oxidative stress
- Neurogenesis and neuroplasticity mechanisms
- Tryptophan and brain disorders
- Pluripotent Stem Cells Research
- MicroRNA in disease regulation
- Prion Diseases and Protein Misfolding
- Barrier Structure and Function Studies
- Autophagy in Disease and Therapy
- Melanoma and MAPK Pathways
- interferon and immune responses
University of California, San Francisco
2021-2025
Institute for Neurodegenerative Disorders
2021-2024
Johns Hopkins Medicine
2017-2024
Johns Hopkins University
2017-2024
Chan Zuckerberg Initiative (United States)
2021-2022
New York University
2022
NYU Langone Health
2019-2022
Neurosciences Institute
2019
Neuroscience Institute
2019
Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between makes it challenging to replicate key findings integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC deeply characterized their genetic properties using whole genome sequencing, genomic stability upon CRISPR-Cas9-based gene editing, including differentiation commonly used types. These studies...
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...
Astrogliosis and activation of microglia are hallmarks prion diseases in humans animals. Both were viewed to be rather independent events disease pathophysiology, with proinflammatory considered the potential neurotoxic species at late stages. Recent investigations have provided substantial evidence that a microglial cytokine cocktail containing TNF-α, IL-1α C1qa reprograms subset astrocytes change their expression profile phenotype, thus becoming (designated as A1-astrocytes). Knockout or...
Abstract Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types represents an unmet clinical need. The mechanisms that mediate metastatic growth the brain parenchyma are largely unknown. Melanoma, which has highest rate among common types, ideal model to study how cells adapt parenchyma. Our unbiased proteomics analysis melanoma short-term cultures revealed proteins implicated neurodegenerative pathologies differentially expressed explanted from...
Abstract Lipid changes in the brain have been implicated many neurodegenerative diseases including Alzheimer’s Disease (AD), Parkinson’s disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named Neurolipid Atlas, that pre-populated with novel human, mouse isogenic induced pluripotent stem cell (iPSC)-derived lipidomics for different diseases. We show iPSC-derived neurons, microglia astrocytes display...
The complexity of the human brain makes it challenging to understand molecular mechanisms underlying function. Genome-wide association studies have uncovered variants associated with neurological phenotypes. Single-cell transcriptomics provided descriptions changes cells undergo during disease. However, these approaches do not establish mechanism. To facilitate scalable interrogation causal in cell types, we developed a 3D co-culture system induced pluripotent stem (iPSC)-derived neurons and...
Glutathione S -transferases in astrocytes enhance microglia activation during brain inflammation.
Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these states, cell biology underlying astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization compartments, decreased autophagic...
Abstract Interleukin (IL)-33 is a member of the IL-1 family cytokines. IL-33 expressed in nuclei and secreted as alarmin upon cellular damage to deliver danger signal surrounding cells. Previous studies showed that brain it involved neuroinflammatory neurodegenerative processes both humans rodents. Nevertheless, role physiological function behavior remains unclear. Here, we have investigated behaviors mice lacking ( Il33 −/− mice). constitutively throughout adult mouse brain, mainly...
Glial cell phagocytosis of pH-dependent amyloid-β, Aβ pH , in live and fixed cultures, brain tissue sections, retina, cortex animals useful for studying function health disease.
To elucidate the impact of Aβ pathology on microglia in Alzheimer's disease pathogenesis, we profiled surfaceome following treatment with fibrils. Our findings reveal that Aβ-associated human upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). In Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating contributes to toxic cellular program during neurodegeneration. cell culture, enhances phagocytosis tau...
Maintaining a dynamic neuronal synapse pool is critical to brain development. The extracellular matrix (ECM) regulates synaptic plasticity via mechanisms that are still being defined and studied predominantly in adulthood. Using live imaging of excitatory synapses zebrafish hindbrain we observed bimodal distribution short-lived (dynamic) longer-lived (stable) synapses. Disruption ECM digestion or brevican deletion destabilized but not stable led decreased density. Conversely, loss...
Chronic stress induces peripheral and intracerebral immune changes inflammation, contributing to neuropathology behavioral abnormalities relevant psychiatric disorders such as depression. Although the pathological implication of many factors pro-inflammatory cytokines, hormones, macrophages has been demonstrated, roles circulating extracellular vesicles (EVs) for chronic mechanisms remain poorly investigated. Here, we report that social defeat (CSDS)-induced avoidance phenotype, assessed by...
ABSTRACT In response to central nervous system injury or disease, astrocytes become reactive, adopting context-dependent states and functional outputs. Certain inflammatory insults induce reactive that lose homeostatic functions gain harmful outputs through cellular pathways are not fully understood. Here, we combined single-cell transcriptomics with CRISPRi screening in human iPSC-derived systematically interrogate astrocyte reactivity. We found autocrine-paracrine IL-6 interferon signaling...
There is a significant need for scalable CRISPR-based genetic screening methods that can be applied directly in mammalian tissues
Summary The sheer complexity of the brain has complicated our ability to understand cellular and molecular mechanisms underlying its function in health disease. Genome-wide association studies have uncovered genetic variants associated with specific neurological phenotypes diseases. In addition, single-cell transcriptomics provided descriptions cell types changes they undergo during Although these approaches provide a giant leap forward towards understanding how variation can lead functional...
Abstract Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease characterized by inflammation, demyelination, and neurodegeneration. The ideal MS therapy would both specifically inhibit the underlying response promote repair/regeneration of myelin as well maintenance axonal integrity. Currently approved therapies consist non‐specific immunosuppressive molecules/antibodies which block activation or CNS homing autoreactive T cells, but there are no for stimulation...
Abstract Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between makes it challenging to replicate key findings integrate data across research groups. To address this issue, we sub-cloned candidate iPSC deeply characterised their genetic properties using whole genome sequencing, genomic stability upon CRISPR/Cas9-based gene editing, including differentiation commonly-used types. These studies...
ABSTRACT Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these states, cell biology underlying astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization compartments, decreased...
Summary Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types represents an unmet clinical need. The mechanisms that mediate metastatic growth the brain parenchyma are largely unknown. Melanoma, which has highest rate among common types, ideal model to study how cells adapt parenchyma. We performed unbiased proteomics analysis melanoma short-term cultures, novel for metastasis. Intriguingly, we found proteins implicated neurodegenerative pathologies...
ABSTRACT Extracellular vesicles (EVs) are cell-derived membrane that circulate throughout the body. Accordingly, circulating EVs and their associated molecules, such as RNAs proteins, regarded promising sources of molecular biomarkers for various disorders. Cell culture-derived have also drawn substantial attention possible delivery tools therapeutic molecules. Nevertheless, biological impact on in vivo physiology pathology remains elusive. Here we report systemic exposure to blood from...