A5074454707- Neuroinflammation and Neurodegeneration Mechanisms
- Epigenetics and DNA Methylation
- Immune cells in cancer
- RNA Research and Splicing
- Ocular Diseases and Behçet’s Syndrome
- Systemic Lupus Erythematosus Research
- interferon and immune responses
- RNA regulation and disease
- Genetics and Neurodevelopmental Disorders
- Neurogenesis and neuroplasticity mechanisms
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Autism Spectrum Disorder Research
- Nuclear Receptors and Signaling
- Diet and metabolism studies
- Protein Degradation and Inhibitors
- Chemokine receptors and signaling
- Adipose Tissue and Metabolism
- Neuroendocrine regulation and behavior
- Peroxisome Proliferator-Activated Receptors
- Genomics and Chromatin Dynamics
- Genetics, Aging, and Longevity in Model Organisms
University of Pennsylvania
2017-2025
Translational Therapeutics (United States)
2017-2025
California University of Pennsylvania
2021
Allen Institute for Brain Science
2016
Icahn School of Medicine at Mount Sinai
2016
Recent studies have implicated epigenetic remodeling in brain reward regions following psychostimulant or stress exposure. It has only recently become possible to target a given type of single gene interest, and probe the functional relevance such regulation neuropsychiatric disease. We sought examine role histone modifications at murine Cdk5 (cyclin-dependent kinase 5) locus, growing evidence expression nucleus accumbens (NAc) influencing reward-related behaviors. Viral-mediated delivery...
Abstract Endogenous homeostatic mechanisms can restore normal neuronal function following cocaine-induced neuroadaptations. Such may be exploited to develop novel therapies for cocaine addiction, but a molecular target has not yet been identified. Here we profiled mouse gene expression during early and late abstinence identify putative regulators of neural homeostasis. Cocaine activated the transcription factor, Nr4a1 , its gene, Cartpt key molecule involved in dopamine metabolism. Sustained...
Hematopoietic stem cell transplantation (HSCT) can replace endogenous microglia with circulation-derived macrophages but has high mortality. To mitigate the risks of HSCT and expand potential for replacement, we engineered an inhibitor-resistant CSF1R that enables robust replacement. A glycine to alanine substitution at position 795 human (G795A) confers resistance multiple inhibitors, including PLX3397 PLX5622. Biochemical cell-based assays show no discernable gain or loss function. G795A-...
Microglia and border-associated macrophages (BAMs) are critical for brain health, their dysfunction is associated to disease. Replacing holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all macrophages. Monocytes readily replaced embryonal BAMs upon depletion engrafted as monocyte-derived microglia (Mo-Microglia) more sustained niche availability. Mo-Microglia expanded comparably embryonic counterparts showed similar...
Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells - a process termed “microglia replacement.” To expand microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized cell model for generation of immune from murine bone marrow, as versatile replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary marrow-derived (BMD) in vitro, and, when transplanted into microglia-free brain,...
Microglia, the brain’s resident macrophages, can be reconstituted by surrogate cells - a process termed “microglia replacement.” To expand microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized cell model for generation of immune from murine bone marrow, as versatile replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary marrow-derived (BMD) in vitro, and, when transplanted into microglia-free brain,...
Chimeric mouse models have recently been developed to study human microglia in vivo. However, widespread engraftment of donor within the adult brain has challenging. Here, we present a protocol introduce G795A point mutation using CRISPR-Cas9 into CSF1R locus pluripotent stem cells. We also describe an optimized microglial differentiation technique for transplantation newborn or recipients. then detail pharmacological paradigms achieve and near-complete microglia. For complete details on use...
Microglia, the brain's resident macrophages, can be reconstituted by surrogate cells - a process termed "microglia replacement." To expand microglia replacement toolkit, we here introduce estrogen-regulated (ER) homeobox B8 (Hoxb8) conditionally immortalized cell model for generation of immune from murine bone marrow, as versatile replacement. We find that ER-Hoxb8 macrophages are highly comparable to primary marrow-derived (BMD) in vitro, and, when transplanted into microglia-free brain,...
ABSTRACT Alternative splicing is a key mechanism for neuronal gene regulation, and grossly altered in mouse brain reward regions following investigator-administered cocaine. It well established that cocaine epigenetically regulates transcription, yet mechanism(s) by which cocaine-induced epigenetic modifications regulate alternative largely unexplored. Our group others have previously identified the histone modification, H3K36me3, as putative regulator. However, it has not been possible to...
Mechanisms by which epigenetic modifications regulate alternative splicing are largely unexplored. Differential and histone modification enrichment key mechanisms for neuronal gene regulation. Both grossly altered in mouse brain following investigator-administered cocaine. Our group others have identified the modification, H3K36me3, as a putative regulator. In current study, we found that cocaine self-administration caused widespread differential splicing, concomitant with of H3K36me3 at...