A5002501996- Prion Diseases and Protein Misfolding
- Cannabis and Cannabinoid Research
- Tryptophan and brain disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Diet and metabolism studies
- Alzheimer's disease research and treatments
- Infectious Encephalopathies and Encephalitis
- Neuroscience and Neuropharmacology Research
- Metabolism and Genetic Disorders
- Trace Elements in Health
- PARP inhibition in cancer therapy
- Pharmacological Receptor Mechanisms and Effects
- Neurological diseases and metabolism
- Supramolecular Self-Assembly in Materials
- Long-Term Effects of COVID-19
- Click Chemistry and Applications
- Neuroscience of respiration and sleep
- Stress Responses and Cortisol
- Forensic Toxicology and Drug Analysis
- Pancreatic function and diabetes
- Immune cells in cancer
- Enzyme Structure and Function
- Advanced Glycation End Products research
- Hereditary Neurological Disorders
- Alcoholism and Thiamine Deficiency
Pfizer (United States)
2012-2022
AbbVie (United States)
2019
Hanover College
2011-2012
Dartmouth College
2011
Dartmouth Hospital
2011
Infectious prions containing the pathogenic conformer of mammalian prion protein (PrP Sc ) can be produced de novo from a mixture normal C with RNA and lipid molecules. Recent reconstitution studies indicate that nucleic acids are not required for propagation mouse in vitro, suggesting existence an alternative cofactor brain tissue. However, identity functional properties this unique unknown. Here, we show by purification molecule responsible nuclease-resistant activity is endogenous...
Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD). Whether anti-inflammatory approaches can be used treat AD, however, major unanswered question. We recently demonstrated monoacylglycerol lipase (MAGL) hydrolyzes...
Prions containing misfolded prion protein (PrP Sc ) can be formed with cofactor molecules using the technique of serial misfolding cyclic amplification. However, it remains unknown whether cofactors materially participate in maintaining conformation and infectious properties. Here we show that withdrawal during propagation purified recombinant prions caused adaptation PrP structure accompanied by a reduction specific infectivity >10 5 -fold, to undetectable levels, despite ability adapted...
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of endocannabinoid 2-arachidonoylglycerol (2-AG) in CNS. MAGL catalyzes conversion 2-AG to arachidonic acid (AA), a precursor proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient inhibitors, identified through parallel medicinal chemistry approach that highlighted improved efficiency azetidine and piperidine-derived carbamates. The discovery optimization 3-substituted carbamate...
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in central nervous system (CNS). Herein we report discovery compound 15 (PF-06795071), potent selective covalent MAGL inhibitor, featuring novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series more lipophilic groups....
Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed infiltration peripheral immune cells, cytotoxic proteins, and water. BBB extravasation these components into brain parenchyma result in oxidative stress, edema, excitotoxicity, neurodegeneration. These downstream consequences dysfunction can drive pathophysiological processes play a substantial role morbidity...
In this study, we tested the hypothesis that glycosylation of pathogenic isoform prion protein (PrP(Sc)) might encode selective neurotropism strains. We prepared unglycosylated cellular (PrP(C)) substrate molecules from normal mouse brain by treatment with PNGase F and used reconstituted serial cyclic misfolding amplification reactions to produce RML 301C prions containing PrP(Sc) molecules. Both RML- 301C-derived were infectious wild-type mice, neuropathological analysis showed mice...
Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures prevent mortality morbidity. Monoacylglycerol lipase (MAGL) the key enzyme responsible for hydrolysis of endocannabinoid 2-arachidonoylglycerol (2-AG) major contributor brain pool arachidonic acid (AA). Inhibiting monoacylglycerol modulates synaptic activity neuroinflammation, 2 mediators excessive neuronal activation underlying seizures. We studied...
Infectious mouse prions can be produced from a mixture of bacterially expressed recombinant prion protein (recPrP), palmitoyloleoylphosphatidylglycerol (POPG), and RNA [Wang, F.; et al. (2010) Science 327, 1132]. In contrast, amyloid fibers pure recPrP without POPG or (recPrP fibers) fail to infect wild type mice [Colby, D.W.; PLoS Pathog. 387, e1000736]. We compared the seeding specificity ultrastructural features infectious (recPrP(Sc)) with those fibers. Our results indicate that PrP are...
Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)-targeted positron emission tomography (PET) has used to assess neuroinflammation major depressive disorder. We aimed 1) test hypothesis significant case-control differences TSPO binding anterior cingulate cortex, prefrontal and insula regions; 2) explore relationship between cerebral peripheral blood C-reactive (CRP) concentration.A total 51 depressed subjects with Hamilton Depression Rating...
Monoacylglycerol lipase (MAGL), a serine hydrolase extensively expressed throughout the brain, serves as key gatekeeper regulating tone of endocannabinoid signaling. Preclinically, inhibition MAGL is known to provide therapeutic benefits for number neurological disorders. The availability MAGL-specific positron emission tomography (PET) ligand would considerably facilitate development and clinical characterization inhibitors via noninvasive quantitative PET imaging. Herein, we report...
Single-stranded polyanions ≥40 bases in length facilitate the formation of hamster scrapie prions vitro, and co-localize with PrPSc aggregates vivo [1], [2]. To test hypothesis that intact polyanionic molecules might serve as a structural backbone essential for maintaining infectious conformation(s) PrPSc, we produced synthetic using photocleavable, 100-base oligonucleotide (PC-oligo). In serial Protein Misfolding Cyclic Amplification (sPMCA) reactions purified PrPC substrate, PC-oligo was...
Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or secondary outcome. For that reason, either diagnostic tools to monitor progression and/or pharmacological interventions, there need for robust biomarkers neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) one few available which are clinically PET imaging agents. In this study, we further characterised mouse model prion-induced chronic neurodegeneration...
Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system. To develop [11C]PF-06809247 into clinically usable MAGL positron emission tomography (PET) radioligand, we assessed occupancy of by an inhibitor in non-human primate (NHP) brain. Additionally, measured whole-body distribution NHP estimated human effective radiation doses. Seven cynomolgus monkeys...
Mature prion protein (PrP) is a 208-residue polypeptide that contains single disulfide bond. We report an alternative method to purify recombinant mouse PrP produced in Escherichia coli. Bacterial inclusion bodies were solubilized buffer containing 2 M urea at pH 12.5. The was rapidly purified on nickel affinity column without chaotrope gradient, followed by ion-exchange chromatography. yield and purity of this approach similar obtained using conventional solubilization on-column refolding...
Abstract Purpose Monoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system (CNS). To develop 11 C-PF-06809247 into clinically usable positron emission tomography (PET) radioligand, we assessed brain target occupancy of MAGL inhibitor using non-human primate (NHP). Additionally, measured whole-body distribution in NHP estimated human effective radiation...
Abstract BackgroundMonoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system (CNS). To develop [ 11 C]PF-06809247 into clinically usable positron emission tomography (PET) radioligand, we assessed brain target occupancy of MAGL inhibitor using non-human primate (NHP). Additionally, measured whole-body distribution in NHP estimated human effective radiation...