A5002907434- Nerve injury and regeneration
- Retinal Development and Disorders
- Glaucoma and retinal disorders
- Retinal Diseases and Treatments
- Glycosylation and Glycoproteins Research
- Neuropeptides and Animal Physiology
- RNA Interference and Gene Delivery
- Signaling Pathways in Disease
- Monoclonal and Polyclonal Antibodies Research
- Neuroblastoma Research and Treatments
- Chemical Synthesis and Analysis
- Neurogenesis and neuroplasticity mechanisms
- Nicotinic Acetylcholine Receptors Study
- Neuroscience and Neuropharmacology Research
- HER2/EGFR in Cancer Research
- Neurological Disorders and Treatments
- Receptor Mechanisms and Signaling
- Immunotherapy and Immune Responses
- Peptidase Inhibition and Analysis
- Immune Cell Function and Interaction
- Alzheimer's disease research and treatments
- Immune Response and Inflammation
- Virus-based gene therapy research
- Cholinesterase and Neurodegenerative Diseases
- Retinoids in leukemia and cellular processes
Jewish General Hospital
2014-2025
McGill University
2016-2025
Otonomy (United States)
2021
Simon Fraser University
2021
University of Helsinki
2020
Biotechnology Research Institute
2000-2014
National Research Council Canada
2014
Therapeutics Clinical Research
1999-2011
Université de Montréal
2005-2009
Pontificia Universidad Católica de Chile
2009
Abstract The heterogeneity of receptor isoforms can cause an apparent paradox where each isoform promote different or even opposite biological pathways. One example is the neurotrophin TrkC. trkC mRNA translates a full-length tyrosine kinase (TrkC-FL) whose activation by growth factor NT3 promotes neuronal survival. In some diseases, spliced to kinase-truncated (TrkC.T1) up-regulates tumor necrosis alpha (TNF-α) causing neurotoxicity. Since TrkC.T1 expression significantly increased at onset...
An enhanced appreciation of uptake mechanisms and intracellular trafficking phosphorothioate modified oligodeoxynucleotides (P-ODN) might facilitate the use these compounds for experimental therapeutic purposes. We addressed issues by identifying cell surface proteins with which P-ODN specifically interact, studying internalization mechanisms, tracking internalized through using immunochemical ultrastructural techniques. Chemical cross-linking studies a biotin-labeled (bP-ODN), revealed...
Recent studies indicate that there is a marked reduction in trkA–containing nucleus basalis neurons end–stage Alzheimer's disease (AD). We used unbiased stereological counting procedures to determine whether these changes extend individuals with mild cognitive impairment (MCI) without dementia from cohort of people enrolled the Religious Orders Study. Thirty (average age 84.7 years) came autopsy. All were cognitively tested within 12 months death MMSE 24.2). Clinically, 9 had no (NCI),...
Abstract Degeneration of cholinergic nucleus basalis (NB) cortical projection neurons is associated with cognitive decline in late‐stage Alzheimer's disease (AD). NB neuron survival dependent on coexpression the nerve growth factor (NGF) receptors p75 NTR and TrkA, which bind NGF sites. We have shown previously a significant reduction perikarya expressing TrkA protein during early stages AD. Whether there concomitant levels these progression AD unknown. was evaluated by quantitative...
HOX, PBX, and MEIS transcription factors bind DNA through a homeodomain. PBX proteins cooperatively as heterodimers with family members also HOX from paralog groups 1 to 10. ABD-B class of 9 Here, we examine aspects dimeric higher-order interactions between these three homeodomain classes. The most significant results can be summarized follows. (i) Most N terminal the is required for efficient cooperative binding HOXD4 HOXD9. (ii) form complexes on heterodimeric site. (iii) Although does not...
In normal adult retinas, NGF receptor TrkA is expressed in retinal ganglion cells (RGC), whereas glia express p75NTR. During injury, endogenous NGF, TrkA, and p75NTR are up-regulated. Paradoxically, neither nor exogenous administration of wild type can protect degenerating RGCs, even when administered at high frequency. Here we elucidate the relative contribution each its receptors to RGC degeneration vivo. due glaucoma or optic nerve transection, treatment with a mutant that only activates...
The prostaglandin F2alpha (PGF2alpha) receptor (FP) is a key regulator of parturition and target for pharmacological management preterm labor. However, an incomplete understanding signaling pathways regulating myometrial contraction hinders the development improved therapeutics. Here we used peptidomimetic inhibitor in mice, PDC113.824, whose structure was based on NH(2)-terminal region second extracellular loop FP receptor, to gain mechanistic insight underlying receptor-mediated cell...
Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in mouse model Alzheimer’s disease.
Melanomas commonly undergo a phenotype switch, from proliferative to an invasive state. Such tumor cell plasticity contributes immunotherapy resistance; however, the mechanisms are not completely understood and thus therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking MNK1/2-eIF4E axis inhibited switching sensitized anti-PD-1 immunotherapy. We showed phospho-eIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results...
Abstract Open angle glaucoma is defined as a progressive and time‐dependent death of retinal ganglion cells concomitant with high intraocular pressure, leading to loss visual field. Because neurotrophins are family growth factors that support neuronal survival, we hypothesized quantitative qualitative changes in or their receptors may take place early ocular hypertension, preceding extensive cell clinical features glaucoma. We present molecular, biochemical, phenotypic evidence significant...
Cholinergic neurons respond to the administration of nerve growth factor (NGF) in vivo with a prominent and selective increase choline acetyl transferase activity. This suggests possible involvement endogenous NGF, acting through its receptor TrkA, maintenance central nervous system cholinergic synapses adult rat brain. To test this hypothesis, small peptide, C(92-96), that blocks NGF-TrkA interactions was delivered stereotactically into cortex over 2-week period, effect potency were...
Small monomeric cyclic analogs that mimic the β-turn regions of nerve growth factor (NGF) were designed and synthesized. Potent competitive antagonists derived from NGF C-D, which inhibited [125I] binding to TrkA receptors specifically optimal NGF-mediated neurite outgrowth in PC12 cells. The A′-A″ analog also but with lower potency. These data indicate β-turns C-D are critical for may confer neurotrophin receptor specificity. Furthermore, structural requirements absolute, because...
Recently, interleukin 2 (IL-2) has been shown to induce increased activity of the p56lck protein-tyrosine kinase (PTK) in T-cell and natural killer cell lines, evidence for a direct interaction between p75 subunit IL-2 receptor (IL-2R) this src-family reported. Though these findings suggest central role lck signal transduction, one problem with idea is that not all IL-2-responsive cells express gene. For reason, we examined effects on src-like kinases pro-B line, F7, lacks but displays...
The murine interleukin 2 (IL-2) receptor is a 55- to 60-kDa glycoprotein (p58) that binds IL-2 at high and low affinity. In this investigation, we have identified sublines of EL4 vary in their capacity express affinity receptors after transfection the cDNA. These other cell populations were used determine whether unique membrane molecules specifically associated with receptor. Irreversible chemical cross-linking [125I]IL-2 only resulted detection cross-linked p58 as 70- 75-kDa band complexes...
Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation the kinase-active Trk receptors and p75 neurotrophin receptor. Truncated receptor isoforms lacking kinase domain are abundantly expressed during development adult; however, function signaling capacity is largely unknown. We show that neurotrophin-3 (NT3) TrkCT1-truncated binds scaffold protein tamalin a ligand-dependent manner. Moreover, NT3 initiation this complex leads...
Brain-derived neurotrophic factor (BDNF) receptors TrkB and p75(NTR) are expressed in the retina. However, exogenous BDNF does not provide retinal ganglion cells (RGCs) with long-lasting neuroprotection vivo during optic nerve axotomy or glaucoma rat models of neurodegeneration. The authors set out to answer hypothesis that a selective agonist might afford more efficient neuroprotection.Animal acute neurodegeneration (complete axotomy) chronic (ocular hypertension, glaucoma) were used. After...
In many diseases, expression and ligand-dependent activity of the p75(NTR) receptor can promote pericyte vascular dysfunction, inflammation, glial activation, neurodegeneration. Diabetic retinopathy (DR) is characterized by all these pathological events. However, mechanisms which may be implicated at each stage DR pathology remain poorly understood. Using a streptozotocin mouse model diabetic retinopathy, we report that upregulated very early in glia pericytes to mediate induction...
A proteolytically stable small molecule beta-turn peptidomimetic, termed D3, was identified as an agonist of the TrkA neurotrophin receptor. D3 binds Ig-like C2 region extracellular domain TrkA, competes binding another agonist, affords selective trophic protection to TrkA-expressing cell lines and neuronal primary cultures, induces differentiation cultures. These results indicate that a peptidomimetic can activate tyrosine kinase receptor normally relatively large protein ligand. Agents...
Nerve growth factor (NGF) receptor-mediated signaling was studied using specific monoclonal antibodies (mAbs) as ligands that discriminate between the receptors TrkA and p75. mAb-induced trophic signals were compared with of natural ligand NGF. In cells expressing but no p75 (TrkA<sup>+</sup>p75<sup>−</sup>), binding mAb 5C3 leads to optimal signals. both (TrkA<sup>+</sup> p75<sup>+</sup>), significant suboptimal signals, are obtained by concomitant mAbs MC192....