A5105926220- Nerve injury and regeneration
- Neurogenesis and neuroplasticity mechanisms
- Neuroblastoma Research and Treatments
- Signaling Pathways in Disease
- Axon Guidance and Neuronal Signaling
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- Cell death mechanisms and regulation
- RNA Research and Splicing
- Cancer, Hypoxia, and Metabolism
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Glioma Diagnosis and Treatment
- Neuroscience and Neuropharmacology Research
- Cancer Research and Treatments
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Protein Tyrosine Phosphatases
- MicroRNA in disease regulation
- Genetics and Neurodevelopmental Disorders
- PI3K/AKT/mTOR signaling in cancer
- HER2/EGFR in Cancer Research
- Nuclear Receptors and Signaling
- Pluripotent Stem Cells Research
- Cytokine Signaling Pathways and Interactions
University of Toronto
2016-2025
SickKids Foundation
2010-2025
Hospital for Sick Children
2016-2025
University of British Columbia
2022-2025
University of British Columbia Hospital
2024
Canada's Michael Smith Genome Sciences Centre
2024
Canada Research Chairs
2007-2020
Great Ormond Street Hospital
2020
University College London
2020
University of Guelph
2015
A signaling pathway was delineated by which insulin-like growth factor 1 (IGF-1) promotes the survival of cerebellar neurons. IGF-1 activation phosphoinositide 3-kinase (PI3-K) triggered two protein kinases, serine-threonine kinase Akt and p70 ribosomal S6 (p70 S6K ). Experiments with pharmacological inhibitors, as well expression wild-type dominant-inhibitory forms Akt, demonstrated that but not mediates PI3-K-dependent survival. These findings suggest in developing nervous system, is a...
The regulation of the serine-threonine kinase Akt by lipid products phosphoinositide 3-kinase (PI 3-kinase) was investigated. activity found to correlate with amount phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P 2 ) in vivo, and synthetic PtdIns-3,4-P activated both vitro vivo. Binding occurred within pleckstrin homology (PH) domain facilitated dimerization Akt. mutated PH not PI vivo or vitro, it impaired binding . Examination other phosphoinositides revealed that they bound much...
In response to NGF, the Trk receptor tyrosine kinase forms a complex with SHC, protein that couples kinases p21ras. Complex formation between and SHC phosphorylation, association of Grb2 were mediated by autophosphorylation at Y490 in (NPQYFSD). To determine role other substrates NGF signaling, receptors mutations Y785 (the PLC-γ1 site) introduced into PC12nnr5 cells. treatment cells expressing either substrate-binding site resulted normal neurite outgrowth Erk1 activity phosphorylation....
p53 plays an essential pro-apoptotic role, a function thought to be shared with its family members p73 and p63. Here, we show that is primarily present in developing neurons as truncated isoform whose levels are dramatically decreased when sympathetic apoptose after nerve growth factor (NGF) withdrawal. Increased expression of rescues these from apoptosis induced by NGF withdrawal or overexpression. In p73–/– mice, all isoforms deleted the greatly enhanced. Thus, anti-apoptotic protein...
The Trp53 gene family member Trp73 encodes two major groups of protein isoforms, TAp73 and ΔNp73, with opposing pro- anti-apoptotic functions; consequently, their relative ratio regulates cell fate. However, the precise roles p73 isoforms in cellular events such as tumor initiation, embryonic development, death remain unclear. To determine which aspects function are attributable to we generated characterized mice exons encoding were specifically deleted create a TAp73-deficient (TAp73 −/− )...
Adult neural stem cells (NSCs) derive from embryonic precursors, but little is known about how or when this occurs. We have addressed issue using single-cell RNA sequencing at multiple developmental time points to analyze the murine cortex, one source of adult forebrain NSCs. computationally identify all major cortical cell types, including radial precursors (RPs) that generate define initial emergence RPs neuroepithelial E11.5. show that, by E13.5, express a transcriptional identity...
Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, presence a stem-like population cells, termed brain tumor-initiating cells (BTIC) that confer resistance conventional therapies.To develop therapeutic strategies target BTICs, we focused on repurposing approach explored already-marketed (clinically approved) drugs for...
Abstract Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that presence macrophages microglia impact tumorigenesis prevent durable response. Herein we identify dual function cytokine IL-33 as an orchestrator microenvironment contributes to tumorigenesis. We find expression in large subset glioma specimens murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In...
Interleukin 3 (IL-3)-dependent survival of hematopoietic cells is known to rely on the activity multiple signaling pathways, including a pathway leading activation phosphoinositide 3-kinase (PI 3-kinase), and protein kinase Akt direct target PI 3-kinase. We find that rapidly induced by cytokine IL-3, suggesting role for in 3-kinase-dependent hematopoetic cells. Dominant-negative mutants specifically block IL-3 interfere with IL-3-dependent proliferation. Overexpression or oncogenic v-akt...