A5103037129- Neutrino Physics Research
- Astrophysics and Cosmic Phenomena
- Dark Matter and Cosmic Phenomena
- Alzheimer's disease research and treatments
- Particle physics theoretical and experimental studies
- Computational Drug Discovery Methods
- Gamma-ray bursts and supernovae
- Particle Detector Development and Performance
- Drug Transport and Resistance Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Tryptophan and brain disorders
- Circadian rhythm and melatonin
- Neuroinflammation and Neurodegeneration Mechanisms
- Receptor Mechanisms and Signaling
- Cholesterol and Lipid Metabolism
- Neuroscience and Neuropharmacology Research
- Catalytic Processes in Materials Science
- Phosphodiesterase function and regulation
- Radiation Detection and Scintillator Technologies
- Pulsars and Gravitational Waves Research
- Amyotrophic Lateral Sclerosis Research
- Cholinesterase and Neurodegenerative Diseases
- Cancer Treatment and Pharmacology
- Atomic and Subatomic Physics Research
- Phenothiazines and Benzothiazines Synthesis and Activities
Istituto Nazionale di Fisica Nucleare, Sezione di Genova
2023-2025
University of Genoa
2023-2025
Mohammed V University
2024
National Institute for Subatomic Physics
2023
Centre National de la Recherche Scientifique
2023
Pfizer (United States)
1996-2020
Akebia Therapeutics (United States)
2019
Beth Israel Deaconess Medical Center
2012
Harvard University
2012
Boston Children's Hospital
2012
The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation is implicated in a number human disorders, including depression, seasonal affective disorder, metabolic disorders. Casein kinase 1 epsilon (CK1ϵ) casein delta (CK1δ) are closely related Ser-Thr protein kinases that serve as key regulators demonstrated by mammalian mutations each dramatically alter period. Therefore, inhibitors CK1δ/ϵ may have utility treating Although we previously...
Abstract Neuroinflammation is a key driver of neurodegenerative disease, however the tools available to model this disease biology at systems level are lacking. We describe translational drug discovery platform based on organotypic culture murine cortical brain slices that recapitulate disease-relevant neuroinflammatory biology. After an acute injury response, assume chronic state marked by transcriptomic profiles indicative activation microglia and astrocytes loss neuronal function....
Circadian rhythms can be entrained by a light-dark (LD) cycle and also reset pharmacologically, for example, the CK1δ/ε inhibitor PF-670462. Here, we determine how these two independent signals affect circadian timekeeping from molecular to behavioral level. By developing systems pharmacology model, predict experimentally validate that chronic inhibition during earlier hours of LD produce constant stable delay rhythm. However, dosing later day, or in presence longer light intervals, is not...
KM3NeT is a Cherenkov-light based neutrino telescope located in the Mediterranean Sea, comprising two detectors ARCA (Sicily, It) and ORCA (Var, Fr). Currently at ∼15% of its total deployment, with completion expected by 2029, it has an energy sensitivity ranging from MeV to PeV. The infrastructure well suited detect astrophysical neutrinos thanks wide field view high duty cycle. In context multi-messenger astronomy, aims quickly reconstructing data identify candidates, both search for...
Casein kinase 1 delta (CK1δ) and casein epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility developing CNS inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided structure-based drug design, potent selective CK1δ/ε have now identified that address this gap, through the design synthesis novel...
Casein kinase 1δ (CK1δ) and 1ε (CK1ε) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On basis our previously published work demonstrating a CK1ε-preferring compound an ineffective clock modulator, we have synthesized series pyrazole-substitued pyridine inhibitors, selective CK1δ isoform. Additionally, using structure-based drug design, been able exploit differences hinge region between p38 find inhibitors that minimal activity. The SAR, brain...
To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated possibility developing a positron emission tomography (PET) radioligand. For this effort, focused design and synthesis efforts on initial CK1δ/ε HTS hits with goal identifying compound that would fulfill set recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as tool meets most key attributes including high MPO desirability score selectivity, penetration, low...
A considerable body of genetic evidence supports the pivotal role γ-secretase in AD. Through proteolytic cleavage APP, enzyme complex is responsible for producing Aβ peptides containing various carboxy-termini. As final step production Aβ, represents a compelling target pharmacological intervention aimed at reducing levels Aβ42, most amyloidogenic isoform, thereby slowing or halting deposition amyloid plaques and subsequent neuronal damage. Our goal was to use novel modulator (GSM) compounds...
The g-secretase complex, which is composed of at least four membrane bound proteins, has an intra-membrane catalytic pore for C-terminal sequence determination the A b peptide. Our goal was to use a g -secretase modulator (GSM) tool compound, GSM-A, further refine how predict efficacy, from in vitro higher order species. Photoaffinity labeling used elucidate target protein within complex. In modulation measured multiple systems: CHO and H4 cells overexpressing wild-type human APP, Tg2576...
Alzheimer's disease (AD) is a debilitating neurodegenerative with no known cure. Apolipoprotein E, (apoE), major lipid transport protein in brain, strongly linked to late onset forms of AD. Of the three human isoforms, apoE4 associated highest risk and apoE2 lowest for developing ApoE has been found play an important role clearance toxic Aß fragments from therefore increasing brain apoE levels could be therapeutic target treating Since also plays as plasma protein, we sought establish...
Compounds that modulate g -secretase (GSMs) activity to selectively lower brain Aβ42 have been pursued as potential therapies for individuals with Alzheimer's disease. The Aβ sequence in humans and guinea pigs is identical but differs from rat. To probe the pharmacodynamic (PD) effects of GSMs, pig seems be a reasonable model; however, rat preferred species since pharmacokinetic (PK) safety characterization conducted Therefore, it critical understand whether exposure-response relationship...
The amyloid hypothesis of Alzheimer's Disease asserts that β-amyloid (Aβ) plays a direct role in the pathogenesis disease. Modulation γ-secretase enzyme represents potentially viable therapeutic approach to reduce pathogenic species Aβ. objectives present study were (1): establish vitro-to-in vivo potency translation for lead chemical series aid SAR understanding, and (2) characterize Aβx-42 lowering potencies two tool compounds via pharmacokinetic/pharmacodynamic (PK/PD) modeling. Male...