Publications by authors named "Anindya Bhattacharya"

85 Publications

Analytical validation and performance characteristics of a 48-gene next-generation sequencing panel for detecting potentially actionable genomic alterations in myeloid neoplasms.

PLoS One 2021 28;16(4):e0243683. Epub 2021 Apr 28.

Department of Advanced Diagnostics, Quest Diagnostics, San Juan Capistrano, CA, United States of America.

Identification of genomic mutations by molecular testing plays an important role in diagnosis, prognosis, and treatment of myeloid neoplasms. Next-generation sequencing (NGS) is an efficient method for simultaneous detection of clinically significant genomic mutations with high sensitivity. Various NGS based in-house developed and commercial myeloid neoplasm panels have been integrated into routine clinical practice. However, some genes frequently mutated in myeloid malignancies are particularly difficult to sequence with NGS panels (e.g., CEBPA, CARL, and FLT3). We report development and validation of a 48-gene NGS panel that includes genes that are technically challenging for molecular profiling of myeloid neoplasms including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). Target regions were captured by hybridization with complementary biotinylated DNA baits, and NGS was performed on an Illumina NextSeq500 instrument. A bioinformatics pipeline that was developed in-house was used to detect single nucleotide variations (SNVs), insertions/deletions (indels), and FLT3 internal tandem duplications (FLT3-ITD). An analytical validation study was performed on 184 unique specimens for variants with allele frequencies ≥5%. Variants identified by the 48-gene panel were compared to those identified by a 35-gene hematologic neoplasms panel using an additional 137 unique specimens. The developed assay was applied to a large cohort (n = 2,053) of patients with suspected myeloid neoplasms. Analytical validation yielded 99.6% sensitivity (95% CI: 98.9-99.9%) and 100% specificity (95% CI: 100%). Concordance of variants detected by the 2 tested panels was 100%. Among patients with suspected myeloid neoplasms (n = 2,053), 54.5% patients harbored at least one clinically significant mutation: 77% in AML patients, 48% in MDS, and 45% in MPN. Together, these findings demonstrate that the assay can identify mutations associated with diagnosis, prognosis, and treatment options of myeloid neoplasms even in technically challenging genes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243683PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081174PMC
April 2021

Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1 female mice.

Dis Model Mech 2020 10 30;13(10). Epub 2020 Oct 30.

Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid 28029, Spain

Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1 murine model. SOD1 mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1 mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1 mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.
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http://dx.doi.org/10.1242/dmm.045732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648608PMC
October 2020

Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties.

J Clin Invest 2020 11;130(11):6158-6170

The α6β4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP's N-terminal region and IRE1α's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.
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http://dx.doi.org/10.1172/JCI140311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598046PMC
November 2020

The antidepressant efficacy of the muscarinic antagonist scopolamine: Past findings and future directions.

Adv Pharmacol 2020 18;89:357-386. Epub 2020 Jun 18.

Janssen R&D, LLC, Neuroscience Therapeutic Area, San Diego, CA, United States. Electronic address:

Scopolamine is a nonselective muscarinic antagonist that has shown relatively rapid antidepressant effects, although to date the results are from limited clinical studies. Scopolamine reportedly has downstream signaling effects thought to be linked to neuroplasticity within glutamatergic synapses and consequent antidepressant action. In psychiatry, clinically validated pathways are unusual and thus merit further research in an effort develop more effect medicines for patients with mood disorders. Thus, we are faced with a unique opportunity to build on the clinical observation associated with scopolamine through reverse translation to identify of targets that retain the clinical efficacy while reducing the side effect profile. This chapter reviews the clinical antidepressant findings with scopolamine, including discussion of differential response across patient subgroups, as well as a review of biomarkers that predict clinical outcome. The preclinical data associated with scopolamine also are reviewed and convey a vision for narrowing in on the therapeutic muscarinic receptor subtype(s) that support the antidepressant effects to guide the development of next generation antimuscarinic drug targets for depression.
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http://dx.doi.org/10.1016/bs.apha.2020.04.002DOI Listing
October 2020

P2X7 receptor antagonists for the treatment of systemic inflammatory disorders.

Prog Med Chem 2020 31;59:63-99. Epub 2020 Jan 31.

Discovery Chemistry, Discovery Sciences, Janssen Research and Development, LLC, San Diego, CA, United States.

P2X7 has continued to be a target of immense interest since it is implicated in several peripheral and central nervous system disorders that result from inflammation. This review primarily describes new P2X7 receptor antagonists that have been investigated and disclosed in patent applications or primary literature since 2015. While a crystal structure of the receptor to aid in the design of novel chemical structures remains elusive, many of the chemotypes that have been disclosed contain similarities, with an amide motif present in all series that have been explored to date. Several of the recent antagonists described are brain penetrant, and two compounds are currently in clinical trials for CNS indications. Additionally, brain penetrant PET ligands have been developed that aid in measuring target engagement and these ligands can potentially be used as biomarkers.
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http://dx.doi.org/10.1016/bs.pmch.2019.11.002DOI Listing
November 2020

Microglial Drug Targets in AD: Opportunities and Challenges in Drug Discovery and Development.

Front Pharmacol 2019 23;10:840. Epub 2019 Aug 23.

AbbVie Foundational Neuroscience Center, Cambridge, MA, United States.

Alzheimer's disease (AD) is a large and increasing unmet medical need with no disease-modifying treatment currently available. Genetic evidence from genome-wide association studies (GWASs) and gene network analysis has clearly revealed a key role of the innate immune system in the brain, of which microglia are the most important element. Single-nucleotide polymorphisms (SNPs) in genes predominantly expressed in microglia have been associated with altered risk of developing AD. Furthermore, microglia-specific pathways are affected on the messenger RNA (mRNA) expression level in post-mortem AD tissue and in mouse models of AD. Together these findings have increased the interest in microglia biology, and numerous scientific reports have proposed microglial molecules and pathways as drug targets for AD. Target identification and validation are generally the first steps in drug discovery. Both target validation and drug lead identification for central nervous system (CNS) targets and diseases entail additional significant obstacles compared to peripheral targets and diseases. This makes CNS drug discovery, even with well-validated targets, challenging. In this article, we will illustrate the special challenges of AD drug discovery by discussing the viability/practicality of possible microglia drug targets including cluster of differentiation 33 (CD33), K3.1, kynurenines, ionotropic P2 receptor 7 (P2X7), programmed death-1 (PD-1), Toll-like receptors (TLRs), and triggering receptor expressed in myeloid cells 2 (TREM2).
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http://dx.doi.org/10.3389/fphar.2019.00840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716448PMC
August 2019

Targeting neuroinflammation with brain penetrant P2X7 antagonists as novel therapeutics for neuropsychiatric disorders.

Neuropsychopharmacology 2020 01 2;45(1):234-235. Epub 2019 Sep 2.

Neuroscience Therapeutic Area, Janssen R&D LLC., Turnhoutseweg 30, Beerse, 2340, Belgium.

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http://dx.doi.org/10.1038/s41386-019-0502-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879571PMC
January 2020

Epigenome-wide association study of DNA methylation and microRNA expression highlights novel pathways for human complex traits.

Epigenetics 2020 Jan - Feb;15(1-2):183-198. Epub 2019 Jul 17.

The National Heart, Lung, and Blood Institute, Boston University's Framingham Heart Study, Framingham, MA, USA.

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at < 0.2. miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 -miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.
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http://dx.doi.org/10.1080/15592294.2019.1640547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961684PMC
April 2021

Pharmacology of JNJ-28583113: A novel TRPM2 antagonist.

Eur J Pharmacol 2019 Jun 6;853:299-307. Epub 2019 Apr 6.

Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA.

Transient receptor potential melastatin type 2 (TRPM2) is a cation channel activated by free intracellular ADP-ribose and reactive oxygen species. TRPM2 signaling has been linked to the pathophysiology of CNS disorders such as neuropathic pain, bipolar disorder and Alzheimer's disease. In this manuscript, we describe the discovery of JNJ-28583113, a potent brain penetrant TRPM2 antagonist. Ca flux assays in cells overexpressing TRPM2 and electrophysiological recordings were used to test the pharmacology of JNJ-28583113. JNJ-28583113 was assayed in vitro on GSK-3 phosphorylation levels, cell death, cytokine release in microglia and unbiased morphological phenotypic analysis. Finally, we dosed animals to evaluate its pharmacokinetic properties. Our results showed that JNJ-28583113 is a potent (126 ± 0.5 nM) TRPM2 antagonist. Blocking TRPM2 caused phosphorylation of GSK3α and β subunits. JNJ-28583113 also protected cells from oxidative stress induced cell death as well as morphological changes induced by non-cytotoxic concentrations of HO. In addition, inhibiting TRPM2 blunted cytokine release in response to pro-inflammatory stimuli in microglia. Lastly, we showed that JNJ-28583113 was brain penetrant but not suitable for systemic dosing as it was rapidly metabolized in vivo. While the in-vitro pharmacology of JNJ-28583113 is the best in class, its in-vivo properties would need optimization to assist in further probing key roles of TRPM2 in CNS pathophysiology.
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http://dx.doi.org/10.1016/j.ejphar.2019.03.043DOI Listing
June 2019

Functional Analysis of Genetic Variants and Somatic Mutations Impacting MicroRNA-Target Recognition: Bioinformatics Resources.

Methods Mol Biol 2019 ;1970:101-120

Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA.

MicroRNAs are small noncoding RNA molecules with great importance in regulating a large number of diverse biological processes in health and disease. MicroRNAs can bind to both coding and noncoding RNAs and regulate their stability and expression. Genetic variants and somatic mutations may alter microRNA sequences and their target sites and therefore impact microRNA-target recognition. Aberrant microRNA-target interactions have been associated with many diseases. In recent years, computational resources have been developed for retrieving, annotating, and analyzing the impact of mutations on microRNA-target recognition. In this chapter, we provide an overview on the computational analysis of mutations impacting microRNA target recognition, followed by a detailed tutorial on how to use three major Web-based bioinformatics resources: PolymiRTS ( http://compbio.uthsc.edu/miRSNP ), a database of genetic variants impacting microRNA target recognition; SomamiR ( http://compbio.uthsc.edu/SomamiR ), a database of somatic mutations affecting the interactions between microRNAs and their targets in mRNAs and noncoding RNAs; and miR2GO ( http://compbio.uthsc.edu/miR2GO ), a computational tool for knowledge-based functional analysis of genetic variants and somatic mutations in microRNA seed regions.
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http://dx.doi.org/10.1007/978-1-4939-9207-2_8DOI Listing
September 2019

Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of F-JNJ-64413739, a PET Radioligand for P2X7 Receptors.

J Nucl Med 2019 08 7;60(8):1154-1159. Epub 2019 Feb 7.

Janssen Research and Development LLC, San Diego, California; and

The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in the brain, and antagonism of the P2X7 receptor is a novel therapeutic strategy to dampen adenosine triphosphate-dependent IL-1β signaling. PET ligands for the P2X7 receptor will not only be valuable to assess central target engagement of drug candidates but also hold promise as surrogate markers of central neuroinflammation. Herein we describe the in vitro and in vivo evaluation of F-JNJ-64413739, an F-labeled PET ligand for imaging the P2X7 receptor in the brain. P2X7 receptor affinity and specificity, pharmacokinetics, metabolic stability, blood-brain barrier permeability, and off-target binding of JNJ-64413739 were evaluated in a series of in vitro, ex vivo, and in vivo assays. F-JNJ-64413739 was radiolabeled via a one-step nucleophilic aromatic substitution. The tracer was also studied in rhesus macaques, and PET images were analyzed with an arterial plasma input function-based Logan graphical analysis. The potency (half-maximal inhibitory concentration) of the P2X7 receptor antagonist JNJ-64413739 is 1.0 ± 0.2 nM and 2.0 ± 0.6 nM at the recombinant human and rat P2X7 receptor, respectively, and the binding affinity is 2.7 nM (rat cortex binding assay) and 15.9 nM (human P2X7 receptor). In nonhuman primate PET imaging studies, dose-dependent receptor occupancy of JNJ-54175446 was observed in 2 rhesus monkeys. At a 0.1 mg/kg dose (intravenous) of JNJ-54175446, the receptor occupancy was calculated to be 17% by Logan graphical analysis, whereas a dose of 2.5 mg/kg yielded a receptor occupancy of 60%. The preclinical evaluation of F-JNJ-64413739 demonstrates that the tracer engages the P2X7 receptor. Reproducible and dose-dependent receptor occupancy studies with the P2X7 receptor antagonist JNJ-54175446 were obtained in rhesus monkeys. This novel PET tracer exhibits in vitro and in vivo characteristics suitable for imaging the P2X7 receptor in the brain and warrants further studies in humans.
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http://dx.doi.org/10.2967/jnumed.118.212696DOI Listing
August 2019

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [F]JNJ-64413739 in a Rat Model of Neuroinflammation.

Mol Imaging Biol 2019 10;21(5):871-878

Janssen Research & Development LLC, 3210 Merryfield Row, San Diego, CA, 92121, USA.

Purpose: The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing a positron emission tomography (PET) tracer for imaging of P2X7 receptors in vivo presents a promising approach to diagnose, monitor, and study neuroinflammation in a variety of brain disorders. To fulfill the goal of developing a P2X7 PET ligand as a biomarker of neuroinflammation, [F]JNJ-64413739 has been recently disclosed.

Procedures: We evaluated [F]JNJ-64413739 in a rat model of neuroinflammation induced by an intracerebral injection of lipopolysaccharide (LPS). In vivo brain uptake was determined by PET imaging. Upregulation of neuroinflammatory biomarkers was determined by quantitative polymerase chain reaction (qPCR). Distribution of the tracer in the brain was determined by ex vivo autoradiography (ARG). The specificity of [F]JNJ-64413739 was confirmed by performing blocking experiments with the P2X7 antagonist JNJ-54175446.

Results: Brain regions of rats injected with LPS had a significantly increased uptake (34 % ± 3 % s.e.m., p = 0.036, t test, standardized uptake value measured over the entire scanning period) of [F]JNJ-64413739 relative to the corresponding brain regions of control animals injected with phosphate-buffered saline (PBS). The uptake in the contralateral regions and cerebellum was not significantly different between the groups of animals. The increase in uptake of [F]JNJ-64413739 at the LPS-injected site observed by PET imaging was concordant with ex vivo ARG, upregulation of neuroinflammatory biomarkers, and elevated P2X7 expression levels.

Conclusions: While further work is needed to study [F]JNJ-64413739 in other types of neuroinflammation, the current results favorably characterize [F]JNJ-64413739 as a potential PET tracer of central neuroinflammation.
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http://dx.doi.org/10.1007/s11307-018-01313-2DOI Listing
October 2019

Isolation and Culture of Astrocytes from Postnatal and Adult Mouse Brains.

Methods Mol Biol 2019 ;1938:37-47

Neuroscience Drug Discovery, Janssen Research and Development, LLC, San Diego, CA, USA.

Astrocytes play fundamental roles in development and plasticity of the central nervous system. Dysfunction of astrocytes contributes to most of neurological diseases ranging from neurodegenerative diseases to psychological disorders. To better understand the involvement of astrocytes in both physiological and pathological conditions, and further elucidate their underlying mechanisms, it is critical to establish a reliable isolation and culture method for the cells. In this chapter, we describe the isolation and culture protocols of astrocytes from postnatal and adult mouse brains.
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http://dx.doi.org/10.1007/978-1-4939-9068-9_3DOI Listing
July 2019

Clinical pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-54175446, a brain permeable P2X7 antagonist, in a randomised single-ascending dose study in healthy participants.

J Psychopharmacol 2018 12 27;32(12):1341-1350. Epub 2018 Sep 27.

1 Janssen Research and Development, Beerse, Belgium.

Background: Central nervous system-derived interleukin-1β plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1β.

Aims: This first-in-human study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants.

Methods: The study had three parts: an ascending-dose study in fasted participants (0.5-300 mg JNJ-54175446); an ascending-dose study in fed participants (50-600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effective concentration (EC) (105 ng/mL) and EC (900 ng/mL) values for central nervous system P2X7 receptor binding.

Results: Seventy-seven participants received a single oral dose of JNJ-54175446 ( n=59) or placebo ( n=18). Area under the curve of concentration time extrapolated to infinity (AUC) increased dose-proportionally; maximum concentration (C) of plasma (C) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest C reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 C in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound C and C were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3'-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1β release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC):82 ng/mL; 95% confidence interval: 48-94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%).

Conclusion: Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1β release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.
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http://dx.doi.org/10.1177/0269881118800067DOI Listing
December 2018

Emerging role of the P2X7-NLRP3-IL1β pathway in mood disorders.

Psychoneuroendocrinology 2018 12 14;98:95-100. Epub 2018 Aug 14.

Neuroscience External Innovation, Johnson & Johnson Innovation Centre, One Chapel Place, London, W1G 0BG, United Kingdom.

The science of neuroimmunopsychiatry has evolved rapidly in the last few years with the hope of tackling the unmet need in mood disorders. This article focuses on an inflammatory pathway, highly conserved in myeloid cells that may play a role in neuroinflammatory disorders including depression. Within the brain tissue, microglia are the myeloid cells that express the P2X7 ion channel that is connected through the NLRP3 inflammasome complex leading to release of IL-1β and IL-18. We present, in the way of reviewing relevant literature, the preclinical data and scientific rationale supporting the role of the P2X7-NLRP3-IL-1β pathway in mood disorders. We also highlight recent advances in drug discovery and development of P2X7 small molecule antagonists and P2X7 PET ligands which provide optimism that clinical tools are availableto address critical proof-of-concept experiments in mood disorders.
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http://dx.doi.org/10.1016/j.psyneuen.2018.08.015DOI Listing
December 2018

Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia.

Neuropsychopharmacology 2018 12 9;43(13):2586-2596. Epub 2018 Jul 9.

Janssen Research & Development, LLC. Neuroscience Therapeutic Area, San Diego, CA, 92131, USA.

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.
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http://dx.doi.org/10.1038/s41386-018-0141-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224414PMC
December 2018

RNA sequencing analysis reveals quiescent microglia isolation methods from postnatal mouse brains and limitations of BV2 cells.

J Neuroinflammation 2018 May 22;15(1):153. Epub 2018 May 22.

Janssen Research & Development, LLC., Neuroscience Drug Discovery, 3210 Merryfield Row, San Diego, CA, 92121, USA.

Background: Microglia play key roles in neuron-glia interaction, neuroinflammation, neural repair, and neurotoxicity. Currently, various microglial in vitro models including primary microglia derived from distinct isolation methods and immortalized microglial cell lines are extensively used. However, the diversity of these existing models raises difficulty in parallel comparison across studies since microglia are sensitive to environmental changes, and thus, different models are likely to show widely varied responses to the same stimuli. To better understand the involvement of microglia in pathophysiological situations, it is critical to establish a reliable microglial model system.

Methods: With postnatal mouse brains, we isolated microglia using three general methods including shaking, mild trypsinization, and CD11b magnetic-associated cell sorting (MACS) and applied RNA sequencing to compare transcriptomes of the isolated cells. Additionally, we generated a genome-wide dataset by RNA sequencing of immortalized BV2 microglial cell line to compare with primary microglia. Furthermore, based on the outcomes of transcriptional analysis, we compared cellular functions between primary microglia and BV2 cells including immune responses to LPS by quantitative RT-PCR and Luminex Multiplex Assay, TGFβ signaling probed by Western blot, and direct migration by chemotaxis assay.

Results: We found that although the yield and purity of microglia were comparable among the three isolation methods, mild trypsinization drove microglia in a relatively active state, evidenced by high amount of amoeboid microglia, enhanced expression of microglial activation genes, and suppression of microglial quiescent genes. In contrast, CD11b MACS was the most reliable and consistent method, and microglia isolated by this method maintained a relatively resting state. Transcriptional and functional analyses revealed that as compared to primary microglia, BV2 cells remain most of the immune functions such as responses to LPS but showed limited TGFβ signaling and chemotaxis upon chemoattractant C5a.

Conclusions: Collectively, we determined the optimal isolation methods for quiescent microglia and characterized the limitations of BV2 cells as an alternative of primary microglia. Considering transcriptional and functional differences, caution should be taken when extrapolating data from various microglial models. In addition, our RNA sequencing database serves as a valuable resource to provide novel insights for appropriate application of microglia as in vitro models.
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http://dx.doi.org/10.1186/s12974-018-1195-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964710PMC
May 2018

Recent Advances in CNS P2X7 Physiology and Pharmacology: Focus on Neuropsychiatric Disorders.

Front Pharmacol 2018 1;9:30. Epub 2018 Feb 1.

Neuroscience Therapeutic Area, Janssen Research and Development, LLC, San Diego, CA, United States.

The ATP-gated P2X7 ion channel is an abundant microglial protein in the CNS that plays an important pathological role in executing ATP-driven danger signal transduction. Emerging data has generated scientific interest and excitement around targeting the P2X7 ion channel as a potential drug target for CNS disorders. Over the past years, a wealth of data has been published on CNS P2X7 biology, in particular the role of P2X7 in microglial cells, and effects of brain-penetrant P2X7 antagonists. Likewise, significant progress has been made around the medicinal chemistry of CNS P2X7 ligands, as antagonists for target validation in models of CNS diseases, to identification of two clinical compounds (JNJ-54175446 and JNJ-55308942) and finally, discovery of P2X7 PET ligands. This review is an attempt to bring together the current understanding of P2X7 in the CNS with a focus on P2X7 as a drug target in neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fphar.2018.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799703PMC
February 2018

Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation.

Sci Rep 2018 01 23;8(1):1468. Epub 2018 Jan 23.

Departments of Pathology, The University of Tennessee Health Science Center, 19 S. Manassas St., Memphis, TN, 38163, USA.

DiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded-RNA-binding protein, participates in the miRNA biogenesis pathway and contributes to miRNA maturation by interacting with the RNAase III enzyme Drosha in cell nuclei. To investigate the role of DGCR8 in vascular smooth muscle cells (VSMCs) at the postnatal stages, we generated tamoxifen-inducible VSMC specific knockout (iKO) mice by crossing DGCR8 with VSMC specific tamoxifen-inducible Cre transgenic mice SMA-Cre-ER. DGCR8iKO mice display reduced body weight one month following tamoxifen treatment and died around 3 months. Blood pressure and vascular reactivity were significantly reduced in DGCR8iKO mice compared to control. Furthermore, loss of DGCR8 in VSMCs inhibited cell proliferation, migration and neointima formation. VSMC differentiation marker genes, including SMA and SM22, were downregulated in DGCR8 iKO mice. The majority of miRNAs were downregulated in DGCR8iKO mice. Disruption of the DGCR8-mediated miRNA biogenesis pathway attenuated multiple signaling pathways including ERK1/2 and AKT. Our results demonstrate that the DGCR8-mediated miRNA pathway is required for maintaining blood pressure, vascular reactivity and vascular wall remodeling at the postnatal stages.
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http://dx.doi.org/10.1038/s41598-018-19660-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780492PMC
January 2018

A Dipolar Cycloaddition Reaction To Access 6-Methyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate.

J Med Chem 2018 01 20;61(1):207-223. Epub 2017 Dec 20.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure-activity relationships of the new compounds are described. Two of these compounds, (S)-(2-fluoro-3-(trifluoromethyl)phenyl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 29) and (S)-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone (compound 35), were found to have robust P2X7 receptor occupancy at low doses in rat with ED values of 0.06 and 0.07 mg/kg, respectively. Compound 35 had notable solubility compared to 29 and showed good tolerability in preclinical species. Compound 35 was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01279DOI Listing
January 2018

OCDD: an obesity and co-morbid disease database.

BioData Min 2017 21;10:33. Epub 2017 Nov 21.

Machine Intelligence Unit, Indian Statistical Institute, 203 B.T. Road, Kolkata, 700108 India.

Background: Obesity is a medical condition that is known for increased body mass index (BMI). It is also associated with chronic low level inflammation. Obesity disrupts the immune-metabolic homeostasis by changing the secretion of adipocytes. This affects the end-organs, and gives rise to several diseases including type 2 diabetes, asthma, non-alcoholic fatty liver diseases and cancers. These diseases are known as co-morbid diseases. Several studies have explored the underlying molecular mechanisms of developing obesity associated comorbid diseases. To understand the development and progression of diseases associated with obesity, we need a detailed scenario of gene interactions and the distribution of the responsible genes in human system.

Results: Obesity and Co-morbid Disease Database (OCDD) is designed for relating obesity and its co-morbid diseases using literature mining, and computational and systems biology approaches. OCDD is aimed to investigate the genes associated with comorbidity. Several existing databases have been used to extract molecular interactions and functional annotations of each gene. The degree of co-morbid associations has been measured and made available to the users. The database is available at http://www.isical.ac.in/~systemsbiology/OCDD/home.php.

Conclusions: The main objective of the database is to derive the relations among the genes that are involved in both obesity and its co-morbid diseases. Functional annotation of common genes, gene interaction networks and key driver analyses have made the database a valuable and comprehensive resource for investigating the causal links between obesity and co-morbid diseases.
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http://dx.doi.org/10.1186/s13040-017-0153-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697160PMC
November 2017

Age-associated microRNA expression in human peripheral blood is associated with all-cause mortality and age-related traits.

Aging Cell 2018 02 17;17(1). Epub 2017 Oct 17.

The Framingham Heart Study, Framingham, MA, USA.

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10 (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases.
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http://dx.doi.org/10.1111/acel.12687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770777PMC
February 2018

The role of microglial P2X7: modulation of cell death and cytokine release.

J Neuroinflammation 2017 07 17;14(1):135. Epub 2017 Jul 17.

Janssen Research & Development, LLC., Neuroscience Drug Discovery, 3210 Merryfield Row, San Diego, CA, 92121, USA.

Background: ATP-gated P2X7 is a non-selective cation channel, which participates in a wide range of cellular functions as well as pathophysiological processes including neuropathic pain, immune response, and neuroinflammation. Despite its abundant expression in microglia, the role of P2X7 in neuroinflammation still remains unclear.

Methods: Primary microglia were isolated from cortices of P0-2 C57BL/6 wild-type or P2X7 knockout (P2X7) mouse pups. Lipopolysaccharide, lipopolysaccharide plus IFNγ, or IL4 plus IL13 were used to polarize microglia to pro-inflammatory or anti-inflammatory states. P2rx7 expression level in resting or activated mouse and human microglia was measured by RNA-sequencing and quantitative real-time PCR. Microglial cell death was measured by cell counting kit-8 and immunocytochemistry, and microglial secretion in wild-type or P2X7 microglia was examined by Luminex multiplex assay or ELISA using P2X7 agonist BzATP or P2X7 antagonist A-804598. P2X7 signaling was analyzed by Western blot.

Results: First, we confirmed that P2rx7 is constitutively expressed in mouse and human primary microglia. Moreover, P2rx7 mRNA level was downregulated in mouse microglia under both pro- and anti-inflammatory conditions. Second, P2X7 agonist BzATP caused cell death of mouse microglia, while this effect was suppressed either by P2X7 knockout or by A-804598 under both basal and pro-inflammatory conditions, which suggests the mediating role of P2X7 in BzATP-induced microglial cell death. Third, BzATP-induced release of IL1 family cytokines including IL1α, IL1β, and IL18 was blocked in P2X7 microglia or by A-804598 in pro-inflammatory microglia, while the release of other cytokines/chemokines was independent of P2X7 activation. These findings support the specific role of P2X7 in IL1 family cytokine release. Finally, P2X7 activation was discovered to be linked to AKT and ERK pathways, which may be the underlying mechanism of P2X7 functions in microglia.

Conclusions: These results reveal that P2X7 mediates BzATP-induced microglial cell death and specific release of IL1 family cytokines, indicating the important role of P2X7 in neuroinflammation and implying the potential of targeting P2X7 for the treatment of neuroinflammatory disorders.
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http://dx.doi.org/10.1186/s12974-017-0904-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513370PMC
July 2017

A GPU-accelerated algorithm for biclustering analysis and detection of condition-dependent coexpression network modules.

Sci Rep 2017 06 23;7(1):4162. Epub 2017 Jun 23.

Department of Microbiology, Immunology and Biochemistry, Memphis, TN, 38163, USA.

In the analysis of large-scale gene expression data, it is important to identify groups of genes with common expression patterns under certain conditions. Many biclustering algorithms have been developed to address this problem. However, comprehensive discovery of functionally coherent biclusters from large datasets remains a challenging problem. Here we propose a GPU-accelerated biclustering algorithm, based on searching for the largest Condition-dependent Correlation Subgroups (CCS) for each gene in the gene expression dataset. We compared CCS with thirteen widely used biclustering algorithms. CCS consistently outperformed all the thirteen biclustering algorithms on both synthetic and real gene expression datasets. As a correlation-based biclustering method, CCS can also be used to find condition-dependent coexpression network modules. We implemented the CCS algorithm using C and implemented the parallelized CCS algorithm using CUDA C for GPU computing. The source code of CCS is available from https://github.com/abhatta3/Condition-dependent-Correlation-Subgroups-CCS.
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http://dx.doi.org/10.1038/s41598-017-04070-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482832PMC
June 2017

Systematic Prediction of the Impacts of Mutations in MicroRNA Seed Sequences.

J Integr Bioinform 2017 May 18;14(1). Epub 2017 May 18.

.

MicroRNAs are a class of small non-coding RNAs that are involved in many important biological processes and the dysfunction of microRNA has been associated with many diseases. The seed region of a microRNA is of crucial importance to its target recognition. Mutations in microRNA seed regions may disrupt the binding of microRNAs to their original target genes and make them bind to new target genes. Here we use a knowledge-based computational method to systematically predict the functional effects of all the possible single nucleotide mutations in human microRNA seed regions. The result provides a comprehensive reference for the functional assessment of the impacts of possible natural and artificial single nucleotide mutations in microRNA seed regions.
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http://dx.doi.org/10.1515/jib-2017-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042800PMC
May 2017

4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

J Med Chem 2017 06 25;60(11):4559-4572. Epub 2017 May 25.

Janssen Research & Development, LLC , 3210 Merryfield Row, San Diego, California 92121, United States.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00408DOI Listing
June 2017

Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice.

Neuropharmacology 2017 04 10;116:351-363. Epub 2017 Jan 10.

Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; Irish Centre for Fetal and Neonatal Translational Research (INFANT) Cork, Ireland. Electronic address:

Neonatal seizures are a common consequence of hypoxic/ischemic encephalopathy (HIE). Phenobarbital remains the frontline treatment for neonatal seizures but is often ineffective. The P2X7 receptor (P2X7R) is a cell surface-expressed ionotropic receptor activated by high amounts of ATP which may be released during seizures or as a consequence of tissue injury. Here, we explored the role of the P2X7R in a mouse model of neonatal seizures induced by hypoxia. Exposure of postnatal day 7 (P7) mouse pups to global hypoxia (5% O for 15 min) produced electrographically-defined seizures with behavioural correlates that persisted after restitution of normoxia. Expression of the P2X7R showed age-dependent increases in the hippocampus and neocortex of developing mice and was present in human neonatal brain. P2X7R transcript and protein levels were increased 24 h after neonatal hypoxia-induced seizures in mouse pups. EEG recordings in pups determined that injection of the P2X7R antagonist A-438079 (25 mg/kg, intraperitoneal) reduced electrographic seizure number, EEG power and spiking during hypoxia. A-438079 did not reduce post-hypoxia seizures. Caspase-1 processing and molecular markers of inflammation and microglia were reduced in A438079-treated mice. Electrographic seizure-suppressive effects were also observed with a second P2X7R antagonist, JNJ-47965567, in the same model. The present study shows hypoxia-induced seizures alter expression of purinergic and neuroinflammatory signalling components and suggest potential applications but also limitations of the P2X7R as a target for the treatment of HIE and other causes of neonatal seizures.
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http://dx.doi.org/10.1016/j.neuropharm.2017.01.005DOI Listing
April 2017

The role of P2X7 receptors in a rodent PCP-induced schizophrenia model.

Sci Rep 2016 11 8;6:36680. Epub 2016 Nov 8.

Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM HAS), H-1450 Budapest, Hungary.

P2X7 receptors (P2X7Rs) are ligand-gated ion channels sensitive to extracellular ATP. Here we examined for the first time the role of P2X7R in an animal model of schizophrenia. Using the PCP induced schizophrenia model we show that both genetic deletion and pharmacological inhibition of P2X7Rs alleviate schizophrenia-like behavioral alterations. In P2rx7+/+ mice, PCP induced hyperlocomotion, stereotype behavior, ataxia and social withdrawal. In P2X7 receptor deficient mice (P2rx7-/-), the social interactions were increased, whereas the PCP induced hyperlocomotion and stereotype behavior were alleviated. The selective P2X7 receptor antagonist JNJ-47965567 partly replicated the effect of gene deficiency on PCP-induced behavioral changes and counteracted PCP-induced social withdrawal. We also show that PCP treatment upregulates and increases the functional responsiveness of P2X7Rs in the prefrontal cortex of young adult animals. The amplitude of NMDA evoked currents recorded from layer V pyramidal neurons of cortical slices were slightly decreased by both genetic deletion of P2rx7 and by JNJ-47965567. PCP induced alterations in mRNA expression encoding schizophrenia-related genes, such as NR2A, NR2B, neuregulin 1, NR1 and GABA α1 subunit were absent in the PFC of young adult P2rx7-/- animals. Our findings point to P2X7R as a potential therapeutic target in schizophrenia.
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http://dx.doi.org/10.1038/srep36680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099752PMC
November 2016

Role of Neuro-Immunological Factors in the Pathophysiology of Mood Disorders: Implications for Novel Therapeutics for Treatment Resistant Depression.

Curr Top Behav Neurosci 2017;31:339-356

Neuroscience, Janssen Research & Development, LLC, Titusville, NJ, 08560, USA.

Mood disorders are associated with persistently high rates of morbidity and mortality, despite the widespread availability of antidepressant treatments. One limitation to extant therapeutic options has been that nearly all approved antidepressant pharmacotherapies exert a similar primary action of blocking monoamine transporters, and few options exist for transitioning treatment resistant patients to alternatives with distinct mechanisms. An emerging area of science that promises novel pathways to antidepressant and mood-stabilizing therapies has followed from evidence that immunological factors play major roles in the pathophysiology of at least some mood disorder subtypes. Here we review evidence that the compounds that reduce the release or signaling of neuroactive cytokines, particularly IL-1β, IL-6, and TNF-α, can exert antidepressant effects in subgroups of depressed patients who are identified by blood-based biomarkers associated with inflammation. Within this context we discuss the role of microglia in central neuroinflammation, and the interaction between the peripheral immune system and the central synaptic microenvironment during and after neuroinflammation. Finally we review data using preclinical neuroinflammation models that produce depression-like behaviors in experimental animals to guide the discovery of novel neuro-immune drug targets.
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http://dx.doi.org/10.1007/7854_2016_43DOI Listing
June 2017

Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration.

BMC Genomics 2016 09 9;17(1):722. Epub 2016 Sep 9.

Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, 90095, USA.

Background: Human diseases are commonly the result of multidimensional changes at molecular, cellular, and systemic levels. Recent advances in genomic technologies have enabled an outpour of omics datasets that capture these changes. However, separate analyses of these various data only provide fragmented understanding and do not capture the holistic view of disease mechanisms. To meet the urgent needs for tools that effectively integrate multiple types of omics data to derive biological insights, we have developed Mergeomics, a computational pipeline that integrates multidimensional disease association data with functional genomics and molecular networks to retrieve biological pathways, gene networks, and central regulators critical for disease development.

Results: To make the Mergeomics pipeline available to a wider research community, we have implemented an online, user-friendly web server ( http://mergeomics.

Research: idre.ucla.edu/ ). The web server features a modular implementation of the Mergeomics pipeline with detailed tutorials. Additionally, it provides curated genomic resources including tissue-specific expression quantitative trait loci, ENCODE functional annotations, biological pathways, and molecular networks, and offers interactive visualization of analytical results. Multiple computational tools including Marker Dependency Filtering (MDF), Marker Set Enrichment Analysis (MSEA), Meta-MSEA, and Weighted Key Driver Analysis (wKDA) can be used separately or in flexible combinations. User-defined summary-level genomic association datasets (e.g., genetic, transcriptomic, epigenomic) related to a particular disease or phenotype can be uploaded and computed real-time to yield biologically interpretable results, which can be viewed online and downloaded for later use.

Conclusions: Our Mergeomics web server offers researchers flexible and user-friendly tools to facilitate integration of multidimensional data into holistic views of disease mechanisms in the form of tissue-specific key regulators, biological pathways, and gene networks.
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http://dx.doi.org/10.1186/s12864-016-3057-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016927PMC
September 2016