A5017834997- Protein Tyrosine Phosphatases
- Cytokine Signaling Pathways and Interactions
- Immune Cell Function and Interaction
- Chronic Lymphocytic Leukemia Research
- Phagocytosis and Immune Regulation
- Galectins and Cancer Biology
- Neuroinflammation and Neurodegeneration Mechanisms
- Chronic Myeloid Leukemia Treatments
- Autophagy in Disease and Therapy
- IL-33, ST2, and ILC Pathways
- interferon and immune responses
- Erythrocyte Function and Pathophysiology
- RNA regulation and disease
- PI3K/AKT/mTOR signaling in cancer
- Multiple Sclerosis Research Studies
- Immune Response and Inflammation
- Calcium signaling and nucleotide metabolism
- Apelin-related biomedical research
- Systemic Lupus Erythematosus Research
- Autoimmune and Inflammatory Disorders Research
- Eosinophilic Esophagitis
- Nerve injury and regeneration
- Chromatin Remodeling and Cancer
- Autoimmune Bullous Skin Diseases
- Peripheral Neuropathies and Disorders
Sanofi (United States)
2018-2024
Sanofi (Belgium)
2022
Albert Einstein College of Medicine
2011-2018
SUNY Upstate Medical University
2006-2015
Yeshiva University
2013
IL-33 is a novel member of the IL-1 cytokine family and potent inducer type 2 immunity, as mast cells Th2 CD4+ T respond to with induction cytokines such IL-13. mRNA levels are extremely high in CNS, CNS glia possess both subunits IL-33R, yet whether produced by affects has not been studied. Here, we demonstrate that pathogen-associated molecular patterns (PAMPs) significantly increase protein expression glia. Interestingly, was localized nucleus astrocytes. Further, glial astrocyte-enriched...
Receptor interacting protein kinase 1 (RIPK1) mediates cell death and inflammatory signaling is increased in multiple sclerosis (MS) brain samples. Here, we investigate the role of glial RIPK1 activity mediating MS pathogenesis. We demonstrate levels correlate with disease progression. find microglia are susceptible to RIPK1-mediated identify an gene signature that may contribute neuroinflammatory milieu patients. uncover a distinct for astrocytes regulating absence confirm...
Tolebrutinib is a covalent BTK inhibitor designed and selected for potency CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied translational approach evaluate three inhibitors Phase 3 clinical development MS with respect their relative block the METHODS: used vitro kinase cellular activation assays, alongside pharmacokinetic sampling of cerebrospinal fluid (CSF) non-human primate cynomolgus estimate ability these candidates (evobrutinib, fenebrutinib,...
Growth arrest-specific protein 6 (GAS6) is a soluble agonist of the TYRO3, AXL, MERTK (TAM) family receptor tyrosine kinases identified to have anti-inflammatory, neuroprotective, and promyelinating properties. During experimental autoimmune encephalomyelitis (EAE), wild-type (WT) mice demonstrate significant induction Gas6 , Axl Mertk but not Pros1 or Tyro3 mRNA. We tested hypothesis that intracerebroventricular delivery GAS6 directly into CNS WT during myelin oligodendrocyte glycoprotein...
Abstract The TAM (Tyro3, Axl, and MerTK) family of receptor tyrosine kinases (RTKs) their ligands, Gas6 ProS1, are important for innate immune responses central nervous system (CNS) homeostasis. While only directly activates ProS1 activation Tyro3/MerTK can indirectly activate Axl through heterodimerization. Therefore, we generated –/– double knockout (DKO) mice to specifically examine the contribution this signaling axis while retaining Tyro3 MerTK. We found that naïve young adult DKO WT...
In response to activation, CD4+ T cells upregulate autophagy. However, the functional consequences of that upregulation have not been fully elucidated. this study, we identify autophagy as a tolerance-avoidance mechanism. Our data show inhibition during cell activation induces long-lasting state hypo-responsiveness is accompanied by expression an anergic gene signature. Cells unable induce after receptor (TCR) engagement inefficient mitochondrial respiration and decreased turnover protein...
Akt is a serine/threonine protein kinase that plays major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved apoptosis insulin signaling respectively, for Akt3 remains uncertain. predominantly expressed brain, total deletion of mice results reduction brain size neurodegeneration following injury. Previously, we found Akt3-/- have significantly worse clinical course during myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune...
AKT3, a member of the serine/threonine kinase AKT family, is involved in variety biologic processes. AKT3 expressed immune cells and major isoform CNS representing 30% total spinal cord, 50% brain. Myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) mouse model which lymphocytes monocytes enter CNS, resulting inflammation, demyelination, axonal injury. We hypothesized that during EAE, deletion would negatively affect AKT3(-/-) mice, making them more...
The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling and inflammatory gene expression, both in the immune system central nervous (CNS). Mice genetically lacking (me/me) display severe demyelinating disease following inoculation with Theiler's murine encephalomyelitis virus (TMEV) compared to infected wild-type mice. Therefore, it became essential investigate mechanisms TMEV-induced inflammation CNS SHP-1-deficient Herein, we show that expression...
Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation multiple sclerosis (MS) but not addressed therapeutically. Bruton's tyrosine kinase (BTK) is expressed both B-lymphocytes and innate immune cells, including microglia, where its role poorly understood. BTK inhibition may provide therapeutic benefit within CNS targeting adaptive immunity-mediated disease progression MS. Using...
We have previously described reduced myelination and corresponding myelin basic protein (MBP) expression in the central nervous system of Src homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice compared with normal littermate controls. Deficiency MBP both brains spinal cords correlated mRNA levels vivo purified oligodendrocytes vitro. Therefore, SHP-1 activity seems to be a critical regulator oligodendrocyte gene function. Consistent this role, study...
We have previously shown that the protein tyrosine phosphatase SHP-1 is highly expressed in CNS glia and an important modulator of cytokine signaling. As such, mice genetically lacking display constitutive myelin abnormalities, severe virus-induced demyelinating disease, defects innate anti-viral responses CNS. In this study, we show differential distribution promoter-specific transcripts demonstrate several cytokines significantly induce expression glia. Consistent with these effects,...
Thursday, April 30April 14, 2020Free AccessCentral Effects of BTK Inhibition in Neuroinflammation (808)Ross C. Gruber, Nathalie Chretien, Michael R. Dufault, Jonathan Proto, Mindy Zhang, LaMorte, Evis Havari, … Show All , Tarek A. Samad, Timothy Turner, Anthony Chomyk, Emilie Christie, Bruce D. Trapp, and Dimitry Ofengeim FewerAuthors Info & AffiliationsApril 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.808 Letters to the Editor
The molecular requirements for human myelination are incompletely defined, and further study is needed to fully understand the cellular mechanisms involved during development in demyelinating diseases. We have established a co-culture model myelination. Our earlier observations showed that addition of γ-carboxylated growth-arrest-specific protein 6 (Gas6) oligodendrocyte progenitor cell (OPC) cultures enhanced their survival maturation. Therefore, we explored effect Gas6 co-cultures enriched...
Abstract The protein tyrosine phosphatase SHP-1 is a critical regulator of cytokine signaling and inflammation. Mice homozygous for null allele at the locus have phenotype severe inflammation are hyper-responsive to TLR4 ligand LPS. stimulation in CNS has been linked both neuropathic pain sickness behaviors. To determine if reduction expression affects LPS-induced behaviors, responses heterozygous SHP-1-deficient (me/+) wild-type (+/+) mice LPS were measured. Chronic (4-week) treatment with...
Abstract Tolebrutinib is a covalent BTK inhibitor designed and selected for potency CNS exposure to optimize impact on BTK-dependent signaling in CNS-resident cells. We applied translational approach evaluate three inhibitors Phase 3 clinical development MS with respect their relative block the CNS, employing vitro kinase, cellular activation assays, pharmacokinetic sampling of cerebrospinal fluid (CSF) non-human primate cynomolgus estimate ability these candidates (evobrutinib,...
Abstract Macroautophagy is a catabolic process whereby cell components, which range from soluble proteins to whole organelles, are sequestered in de novo formed double-membrane autophagosomes that fuse with lysosomes degrade their cargo. Effector T helper cells induce macroautophagy during activation maintain proliferation and cytokine production. unable upregulate activity show reduction ATP generation, suggesting necessary the energy metabolism required meet demands of activation. It...
To characterize the pharmacokinetic properties of central nervous system (CNS)–penetrant Bruton's tyrosine kinase (BTK) inhibitor tolebrutinib, its effects on microglia, and potential to modulate disease progression in MS.