Publications by authors named "Lawrence J Marnett"

260 Publications

In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity.

Neuron 2021 08;109(15):2398-2403.e4

Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.

The brain's endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling in vivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling in vivo.
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http://dx.doi.org/10.1016/j.neuron.2021.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351909PMC
August 2021

Targeting diacylglycerol lipase reduces alcohol consumption in preclinical models.

J Clin Invest 2021 Jul 22. Epub 2021 Jul 22.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, United States of America.

Alcohol use disorder (AUD) is associated with substantial morbidity, mortality, and societal cost, and pharmacological treatment options for AUD are limited. The endogenous cannabinoid (eCB) signaling system is critically involved in reward processing and alcohol intake is positively correlated with release of the eCB ligand 2-Arachidonoylglycerol (2-AG) within reward neurocircuitry. Here we show that genetic and pharmacological inhibition of diacylglycerol lipase (DAGL), the rate limiting enzyme in the synthesis of 2-AG, reduces alcohol consumption in a variety of preclinical models ranging from a voluntary free-access model to aversion resistant-drinking and dependence-like drinking induced via chronic intermittent ethanol vapor exposure in mice. DAGL inhibition during either chronic alcohol consumption or protracted withdrawal was devoid of anxiogenic and depressive-like behavioral effects. Lastly, DAGL inhibition also prevented ethanol-induced suppression of GABAergic transmission onto midbrain dopamine neurons, providing mechanistic insight into how DAGL inhibition could affect alcohol reward. These data suggest reducing 2-AG signaling via inhibition of DAGL could represent an effective approach to reduce alcohol consumption across the spectrum of AUD severity.
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http://dx.doi.org/10.1172/JCI146861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409586PMC
July 2021

Harmaline Analogs as Substrate-Selective Cyclooxygenase-2 Inhibitors.

ACS Med Chem Lett 2020 Oct 14;11(10):1881-1885. Epub 2020 Feb 14.

A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.

We report the design, synthesis, and evaluation of a series of harmaline analogs as selective inhibitors of 2-arachidonylglycerol (2-AG) oxygenation over arachidonic acid (AA) oxygenation by purified cyclooxygenase-2 (COX-2). A fused tricyclic harmaline analog containing a CHO substituent at C-6 and a CH group at the C-1 position of 4,9-dihydro-3-pyrido[3,4-]indole (compound ) was the best substrate-selective COX-2 inhibitor of those evaluated, exhibiting a 2AG-selective COX-2 inhibitory IC of 0.022 μM as compared to >1 μM for AA. The 2.66 Å resolution crystal complex of COX-2 with compound revealed that this series of tricyclic indoles binds in the cyclooxygenase channel by flipping the side chain of L531 toward the dimer interface. This novel tricyclic indole series provides the foundation for the development of promising substrate-selective molecules capable of increasing endocannabinoid (EC) levels in the brain to offer new treatments for a variety of diseases, from pain and inflammation to stress and anxiety disorders.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549255PMC
October 2020

Molecular Imaging of Inflammation in Osteoarthritis Using a Water-Soluble Fluorocoxib.

ACS Med Chem Lett 2020 Oct 24;11(10):1875-1880. Epub 2020 Feb 24.

A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.

Clinical imaging approaches to detect inflammatory biomarkers, such as cyclooxygenase-2 (COX-2), may facilitate the diagnosis and therapy of inflammatory diseases. To this end, we report the discovery of -[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-indol-3-yl]acetamide chloride salt (fluorocoxib D), a hydrophilic analog of fluorocoxib A. Fluorocoxib D inhibits COX-2 selectively in purified enzyme preparations and cells. It exhibits adequate photophysical properties to enable detection of COX-2 in intact cells, in a mouse model of carrageenan-induced acute footpad inflammation and inflammation in a mouse model of osteoarthritis. COX-2-selectivity was verified either by blocking the enzyme's active site with celecoxib or by molecular imaging with nontargeted 5-carboxy-X-rhodamine dye. These data indicate that fluorocoxib D is an ideal candidate for early detection of inflammatory or neoplastic lesions expressing elevated levels of COX-2.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549260PMC
October 2020

Pharmacokinetic characterization of fluorocoxib D, a cyclooxygenase-2-targeted optical imaging agent for detection of cancer.

J Biomed Opt 2020 08;25(8)

Vanderbilt University School of Medicine, Vanderbilt Institute of Chemical Biology, Center for Molec, United States.

Significance: Fluorocoxib D, N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, is a water-soluble optical imaging agent to detect cyclooxygenase-2 (COX-2)-expressing cancer cells.

Aim: We evaluated the pharmacokinetic and safety properties of fluorocoxib D and its ability to detect cancer cells in vitro and in vivo.

Approach: Pharmacokinetic parameters of fluorocoxib D were assessed from plasma collected at designated time points after intravenous administration of 1  mg  /  kg fluorocoxib D in six research dogs using a high-performance liquid chromatography analysis. Safety of fluorocoxib D was assessed for 3 days after its administration using physical assessment, complete blood count, serum chemistry profile, and complete urinalysis in six research dogs. The ability of fluorocoxib D to detect COX-2-expressing cancer cells was performed using human 5637 cells in vitro and during rhinoscopy evaluation of specific fluorocoxib D uptake by canine cancer cells in vivo.

Results: No evidence of toxicity and no clinically relevant adverse events were noted in dogs. Peak concentration of fluorocoxib D (114.8  ±  50.5  ng  /  ml) was detected in plasma collected at 0.5 h after its administration. Pretreatment of celecoxib blocked specific uptake of fluorocoxib D in COX-2-expressing human 5637 cancer cells. Fluorocoxib D uptake was detected in histology-confirmed COX-2-expressing head and neck cancer during rhinoscopy in a client-owned dog in vivo. Specific tumor-to-normal tissue ratio of detected fluorocoxib D signal was in an average of 3.7  ±  0.9 using Image J analysis.

Conclusions: Our results suggest that fluorocoxib D is a safe optical imaging agent used for detection of COX-2-expressing cancers and their margins during image-guided minimally invasive biopsy and surgical procedures.
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http://dx.doi.org/10.1117/1.JBO.25.8.086005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456637PMC
August 2020

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Gut 2021 03 8;70(3):555-566. Epub 2020 Jul 8.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Objective: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.

Design: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs).

Results: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.

Conclusions: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity.

Trial Registration Number: gov Identifier: NCT02052908.
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http://dx.doi.org/10.1136/gutjnl-2020-320946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790993PMC
March 2021

Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa.

Gut 2021 03 8;70(3):555-566. Epub 2020 Jul 8.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Objective: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS.

Design: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs).

Results: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control.

Conclusions: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity.

Trial Registration Number: gov Identifier: NCT02052908.
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http://dx.doi.org/10.1136/gutjnl-2020-320946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790993PMC
March 2021

Adventures with Bruce Ames and the Ames test.

Mutat Res Genet Toxicol Environ Mutagen 2019 Oct 4;846:403070. Epub 2019 Jul 4.

Departments of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville TN 37240-7914, United States. Electronic address:

Bruce Ames has had an enormous impact on human health by developing facile methods for the identification of mutagens. This research also provided important insights into the relationship between mutagenesis and carcinogenesis. Bruce is a highly innovative and creative individual who has followed his interests across disciplines into diverse fields of inquiry. The present author had the pleasure of spending a sabbatical in the Ames lab and utilized the Ames test in multiple aspects of his research. He describes both in this honorific to Bruce on the occasion of his 90 birthday.
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http://dx.doi.org/10.1016/j.mrgentox.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779344PMC
October 2019

Aspects of Prostaglandin Glycerol Ester Biology.

Adv Exp Med Biol 2019 ;1161:77-88

A. B. Hancock Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA.

The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much work has been done showing that COX-2 will perform this reaction on several different AA-containing molecules, most importantly, the endocannabinoid 2-arachidonoylglycerol (2-AG). The products of 2-AG oxygenation, prostaglandin glycerol esters (PG-Gs), are analogous to canonical prostaglandins. This chapter reviews the literature detailing the production, metabolism, and bioactivity of these compounds, as well as their detection in intact animals.
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http://dx.doi.org/10.1007/978-3-030-21735-8_8DOI Listing
October 2019

Signal integration and information transfer in an allosterically regulated network.

NPJ Syst Biol Appl 2019 18;5:23. Epub 2019 Jul 18.

1Department of Biochemistry, Vanderbilt University, Nashville, TN 37212 USA.

A biological reaction network may serve multiple purposes, processing more than one input and impacting downstream processes via more than one output. These networks operate in a dynamic cellular environment in which the levels of network components may change within cells and across cells. Recent evidence suggests that protein concentration variability could explain cell fate decisions. However, systems with multiple inputs, multiple outputs, and changing input concentrations have not been studied in detail due to their complexity. Here, we take a systems biochemistry approach, combining physiochemical modeling and information theory, to investigate how cyclooxygenase-2 (COX-2) processes simultaneous input signals within a complex interaction network. We find that changes in input levels affect the amount of information transmitted by the network, as does the correlation between those inputs. This, and the allosteric regulation of COX-2 by its substrates, allows it to act as a signal integrator that is most sensitive to changes in relative input levels.
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http://dx.doi.org/10.1038/s41540-019-0100-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639376PMC
April 2020

Targeted Detection of Cyclooxygenase-1 in Ovarian Cancer.

ACS Med Chem Lett 2020 Oct 24;11(10):1837-1842. Epub 2019 Jul 24.

A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 United States.

Overexpression of cyclooxygenase-1 (COX-1) is associated with the initiation and progression of ovarian cancer, and targeted imaging of COX-1 is a promising strategy for early detection of this disease. We report the discovery of -[(5-carboxy-X-rhodaminyl)but-4-yl]-3-(1-(4-methoxyphenyl)-5-(-tolyl)-1-pyrazol-3-yl)propenamide (CMP) as the first COX-1-targeted optical agent for imaging of ovarian cancer. CMP exhibits light emission at 604 nm (λ), thereby minimizing tissue autofluorescence interference. In both purified enzyme and COX-1-expressing human ovarian adenocarcinoma (OVCAR-3) cells, CMP inhibits COX-1 at low nanomolar potencies (IC = 94 and 44 nM, respectively). CMP's selective binding to COX-1 in OVCAR-3 cells was visualized microscopically as intense intracellular fluorescence. optical imaging of xenografts in athymic nude mice revealed COX-1-dependent accumulation of CMP in COX-1-expressing mouse ovarian surface epithelial carcinoma (ID8-NGL) and OVCAR-3 cells. These results establish proof-of-principle for the feasibility of targeting COX-1 in the development of new imaging and therapeutic strategies for ovarian cancer.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549111PMC
October 2020

IRE1α-XBP1 signaling in leukocytes controls prostaglandin biosynthesis and pain.

Science 2019 07;365(6450)

Weill Cornell Graduate School of Medical Sciences, Cornell University. New York, NY 10065, USA.

Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
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http://dx.doi.org/10.1126/science.aau6499DOI Listing
July 2019

Targeting COX-1 by mofezolac-based fluorescent probes for ovarian cancer detection.

Eur J Med Chem 2019 Oct 15;179:16-25. Epub 2019 Jun 15.

Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", Via E. Orabona 4, 70125, Bari, Italy. Electronic address:

Biomarkers of specific targets are becoming an essential objective for clinical unmet clinical needs to improve diseases early detection and increase patient overall survival. Ovarian cancer is among the highest mortality gynecological cancers. It is asymptomatic and almost always diagnosed at advanced stage. At five years from the first diagnosis the survival rate of ovarian cancer patients is only 30%. Cyclooxygenase (COX)-1 as opposed to COX-2 is known to be overexpressed in ovarian cancer. Therefore, fluorescent probes targeting COX-1 were designed and prepared in fair to good yields for its quantitatively detection in human ovarian cancer cell lines (OVCAR-3 and SKOV-3). In particular, both cytofluorimetric and immunofluorescent experiments showed that N-[4-(9-dimethylimino-9H-benzo[a]phenoxazin-5-ylamino)butyl]-2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetamide chloride (11) enters into OVCAR-3 cells and is mainly localized on the membrane containing the COX-1. Membrane fluorescence emission represents about 80% of the total fluorescence measured in the whole cell, while the non-specific labeling represents only 20%. This result indicates that the intensity of fluorescence emission is almost exclusively attributable to 11 bound to COX-1 located on the membrane. Furthermore, no diffusion inside the cell occurs. IChCOX-1 value of 11 determined by measuring the O consumption during the bis-oxygenation of the arachidonic acid catalysed by COX-1 was found to be equal to 1.8 nM. Furthermore, 11 inhibits oCOX-1 with IC = 6.85 nM and mCOX-2 with IC = 269.5 nM; the corresponding selectivity index SI is equal to 39.3 against oCOX-1. 11 inhibits oCOX-1 at 0 min of incubation with 91% inhibition, whereas in the same time it does not inhibit mCOX-2. Fingerprints for Ligands and Proteins (FLAP) software calculations were performed to justify 11 higher COX-1 inhibitory potency than mofezolac (COX-1 IC = 5.1 nM), which in turn is a moiety of 11. Specifically, the two compounds bind differently in the COX-1 active site.
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http://dx.doi.org/10.1016/j.ejmech.2019.06.039DOI Listing
October 2019

Discovery of Furanone-Based Radiopharmaceuticals for Diagnostic Targeting of COX-1 in Ovarian Cancer.

ACS Omega 2019 May 24;4(5):9251-9261. Epub 2019 May 24.

A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt-Ingram Cancer Center, and Department of Radiology and Radiological Sciences, Vanderbilt Institute of Imaging Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.

In vivo targeting and visualization of cyclooxygenase-1 (COX-1) using multimodal positron emission tomography/computed tomography imaging represents a unique opportunity for early detection and/or therapeutic evaluation of ovarian cancer because overexpression of COX-1 has been characterized as a pathologic hallmark of the initiation and progression of this disease. The furanone core is a common building block of many synthetic and natural products that exhibit a wide range of biological activities. We hypothesize that furanone-based COX-1 inhibitors can be designed as imaging agents for the early detection, delineation of tumor margin, and evaluation of treatment response of ovarian cancer. We report the discovery of 3-(4-fluorophenyl)-5,5-dimethyl-4-(-tolyl)furan-2(5)-one (FDF), a furanone-based novel COX-1-selective inhibitor that exhibits adequate in vivo stability, plasma half-life, and pharmacokinetic properties for use as an imaging agent. We describe a novel synthetic scheme in which a Lewis acid-catalyzed nucleophilic aromatic deiodo[F]fluorination reaction is utilized for the radiosynthesis of [F]FDF. [F]FDF binds efficiently to COX-1 in vivo and enables sensitive detection of ovarian cancer in subcutaneous and peritoneal xenograft models in mice. These results provide the proof of principle for COX-1-targeted imaging of ovarian cancer and identify [F]FDF as a promising lead compound for further preclinical and clinical development.
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http://dx.doi.org/10.1021/acsomega.9b01093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545551PMC
May 2019

Fluorescent indomethacin-dansyl conjugates utilize the membrane-binding domain of cyclooxygenase-2 to block the opening to the active site.

J Biol Chem 2019 05 18;294(22):8690-8698. Epub 2019 Apr 18.

From the A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,

Many indomethacin amides and esters are cyclooxygenase-2 (COX-2)-selective inhibitors, providing a framework for the design of COX-2-targeted imaging and cancer chemotherapeutic agents. Although previous studies have suggested that the amide or ester moiety of these inhibitors binds in the lobby region, a spacious alcove within the enzyme's membrane-binding domain, structural details have been lacking. Here, we present observations on the crystal complexes of COX-2 with two indomethacin-dansyl conjugates (compounds 1 and 2) at 2.22-Å resolution. Both compounds are COX-2-selective inhibitors with IC values of 0.76 and 0.17 μm, respectively. Our results confirmed that the dansyl moiety is localized in and establishes hydrophobic interactions and several hydrogen bonds with the lobby of the membrane-binding domain. We noted that in both crystal structures, the linker tethering indomethacin to the dansyl moiety passes through the constriction at the mouth of the COX-2 active site, resulting in displacement and disorder of Arg-120, located at the opening to the active site. Both compounds exhibited higher inhibitory potency against a COX-2 R120A variant than against the WT enzyme. Inhibition kinetics of compound 2 were similar to those of the indomethacin parent compound against WT COX-2, and the R120A substitution reduced the time dependence of COX inhibition. These results provide a structural basis for the further design and optimization of conjugated COX reagents for imaging of malignant or inflammatory tissues containing high COX-2 levels.
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http://dx.doi.org/10.1074/jbc.RA119.007405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552414PMC
May 2019

Lysophospholipases cooperate to mediate lipid homeostasis and lysophospholipid signaling.

J Lipid Res 2019 02 27;60(2):360-374. Epub 2018 Nov 27.

A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Departments of Chemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146

Lysophospholipids (LysoPLs) are bioactive lipid species involved in cellular signaling processes and the regulation of cell membrane structure. LysoPLs are metabolized through the action of lysophospholipases, including lysophospholipase A1 (LYPLA1) and lysophospholipase A2 (LYPLA2). A new X-ray crystal structure of LYPLA2 compared with a previously published structure of LYPLA1 demonstrated near-identical folding of the two enzymes; however, LYPLA1 and LYPLA2 have displayed distinct substrate specificities in recombinant enzyme assays. To determine how these in vitro substrate preferences translate into a relevant cellular setting and better understand the enzymes' role in LysoPL metabolism, CRISPR-Cas9 technology was utilized to generate stable KOs of and/or in Neuro2a cells. Using these cellular models in combination with a targeted lipidomics approach, LysoPL levels were quantified and compared between cell lines to determine the effect of losing lysophospholipase activity on lipid metabolism. This work suggests that LYPLA1 and LYPLA2 are each able to account for the loss of the other to maintain lipid homeostasis in cells; however, when both are deleted, LysoPL levels are dramatically increased, causing phenotypic and morphological changes to the cells.
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http://dx.doi.org/10.1194/jlr.M087890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358295PMC
February 2019

( R)- N-(1-Methyl-2-hydroxyethyl)-13-( S)-methyl-arachidonamide (AMG315): A Novel Chiral Potent Endocannabinoid Ligand with Stability to Metabolizing Enzymes.

J Med Chem 2018 10 21;61(19):8639-8657. Epub 2018 Sep 21.

Center for Drug Discovery and Department of Pharmaceutical Sciences , Northeastern University , Boston , Massachusetts 02115 , United States.

The synthesis of potent metabolically stable endocannabinoids is challenging. Here we report a chiral arachidonoyl ethanolamide (AEA) analogue, namely, (13 S,1' R)-dimethylanandamide (AMG315, 3a), a high affinity ligand for the CB1 receptor ( K of 7.8 ± 1.4 nM) that behaves as a potent CB1 agonist in vitro (EC = 0.6 ± 0.2 nM). (13 S,1' R)-dimethylanandamide is the first potent AEA analogue with significant stability for all endocannabinoid hydrolyzing enzymes as well as the oxidative enzymes COX-2. When tested in vivo using the CFA-induced inflammatory pain model, 3a behaved as a more potent analgesic when compared to endogenous AEA or its hydrolytically stable analogue AM356. This novel analogue will serve as a very useful endocannabinoid probe.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00611DOI Listing
October 2018

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks.

Proc Natl Acad Sci U S A 2018 09 27;115(37):9228-9233. Epub 2018 Aug 27.

A.B. Hancock Memorial Laboratory for Cancer Research, Vanderbilt University, Nashville, TN 37232;

Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code. Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation. Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO). Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation. These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding. In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications. Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1. Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO. Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism.
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http://dx.doi.org/10.1073/pnas.1802901115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140490PMC
September 2018

Inhibition of Diacylglycerol Lipase Impairs Fear Extinction in Mice.

Front Neurosci 2018 31;12:479. Epub 2018 Jul 31.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States.

Elucidating the underlying molecular mechanisms regulating fear and extinction learning may offer insights that can lead to novel treatments for debilitating anxiety and trauma-related disorders including posttraumatic stress disorder. The endocannabinoid (eCB) system is a retrograde inhibitory signaling pathway involved in regulating central responses to stress. The eCB 2-arachidonoylglycerol (2-AG) has recently been proposed to serve as a homeostatic signal mitigating adverse effects of stress exposure, however, less well understood is 2-AG's role in fear learning and fear extinction. In this study, we have sought to explore 2-AG's role in fear conditioning and fear extinction by disrupting 2-AG synthesis utilizing the DAGL inhibitor (DO34) and DAGLα knock-out mice (DAGLα). We found that DAGLα mice, and male and female C57B6/J mice treated with DO34, exhibited impairment in extinction learning in an auditory cue fear-conditioning paradigm. DO34 did not increase unconditioned freezing. Interestingly, inhibition of fatty-acid amide hydrolase was not able to restore normal fear extinction in DO34-treated mice suggesting increased Anandamide cannot compensate for deficient 2-AG signaling in the regulation of fear extinction. Moreover, augmentation of CB1R signaling with tetrahydrocannabinol also failed to restore normal fear extinction in DO34-treated mice. Overall, these data support the hypothesis that DAGLα plays an important role in fear extinction learning. Although genetic and pharmacological disruption of DAGL activity causes widespread lipidomic remodeling, these data combined with previous studies putatively suggest that deficient 2-AG signaling could be a susceptibility endophenotype for the development of trauma-related psychiatric disorders.
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http://dx.doi.org/10.3389/fnins.2018.00479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080414PMC
July 2018

Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain.

ACS Chem Neurosci 2018 07 9;9(7):1552-1559. Epub 2018 May 9.

Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX-2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs.
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http://dx.doi.org/10.1021/acschemneuro.7b00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081739PMC
July 2018

Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.

Transl Psychiatry 2018 04 26;8(1):92. Epub 2018 Apr 26.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.

Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.
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http://dx.doi.org/10.1038/s41398-018-0141-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5917016PMC
April 2018

Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors.

J Ovarian Res 2018 Feb 27;11(1):17. Epub 2018 Feb 27.

Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, The University of Kansas Medical Center, MS 2028, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.

Background: High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors.

Methods: We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression.

Results: Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53).

Conclusions: These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.
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http://dx.doi.org/10.1186/s13048-018-0389-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828488PMC
February 2018

Oxidative stress increases M1dG, a major peroxidation-derived DNA adduct, in mitochondrial DNA.

Nucleic Acids Res 2018 04;46(7):3458-3467

A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.

Reactive oxygen species (ROS) are formed in mitochondria during electron transport and energy generation. Elevated levels of ROS lead to increased amounts of mitochondrial DNA (mtDNA) damage. We report that levels of M1dG, a major endogenous peroxidation-derived DNA adduct, are 50-100-fold higher in mtDNA than in nuclear DNA in several different human cell lines. Treatment of cells with agents that either increase or decrease mitochondrial superoxide levels leads to increased or decreased levels of M1dG in mtDNA, respectively. Sequence analysis of adducted mtDNA suggests that M1dG residues are randomly distributed throughout the mitochondrial genome. Basal levels of M1dG in mtDNA from pulmonary microvascular endothelial cells (PMVECs) from transgenic bone morphogenetic protein receptor 2 mutant mice (BMPR2R899X) (four adducts per 106 dG) are twice as high as adduct levels in wild-type cells. A similar increase was observed in mtDNA from heterozygous null (BMPR2+/-) compared to wild-type PMVECs. Pulmonary arterial hypertension is observed in the presence of BMPR2 signaling disruptions, which are also associated with mitochondrial dysfunction and oxidant injury to endothelial tissue. Persistence of M1dG adducts in mtDNA could have implications for mutagenesis and mitochondrial gene expression, thereby contributing to the role of mitochondrial dysfunction in diseases.
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http://dx.doi.org/10.1093/nar/gky089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909422PMC
April 2018

Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.

J Biol Chem 2018 03 11;293(9):3028-3038. Epub 2018 Jan 11.

From the A. B. Hancock, Jr. Memorial Laboratory for Cancer Research, Departments of Biochemistry, Chemistry, and Pharmacology, Vanderbilt Institute of Chemical Biology and Center in Molecular Toxicology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,

The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H (PGH). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·()-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, ()-ARN2508 is more potent than ()-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to ()-flurbiprofen, ()-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for ()-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of ()-flurbiprofen.
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http://dx.doi.org/10.1074/jbc.M117.802058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836124PMC
March 2018

Protein Modification by Endogenously Generated Lipid Electrophiles: Mitochondria as the Source and Target.

ACS Chem Biol 2017 08 28;12(8):2062-2069. Epub 2017 Jun 28.

A.B. Hancock Memorial Laboratory for Cancer Research, Departments of Chemistry, ‡Biochemistry, §Pharmacology, ∥Biomedical Informatics, ⊥Vanderbilt Mass Spectrometry Research Center, Vanderbilt Institute for Chemical Biology, Vanderbilt Center in Molecular Toxicology, Vanderbilt Ingram Cancer Center, Vanderbilt University , Nashville, Tennessee 37232, United States.

Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω-alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo-lipid A, followed by protein extraction, click chemistry, and streptavidin affinity capture, enabled a systems-level survey of proteins adducted by lipid electrophiles generated endogenously during the inflammatory response. Results revealed a dramatic enrichment for membrane and mitochondrial proteins as targets for adduction. A marked decrease in adduction in the presence of MitoTEMPO demonstrated a primary role for mitochondrial superoxide in electrophile generation and indicated an important role for mitochondria as both a source and target of lipid electrophiles, a finding that has not been revealed by prior studies using exogenously provided electrophiles.
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http://dx.doi.org/10.1021/acschembio.7b00480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174696PMC
August 2017

Prostaglandin E glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y.

Sci Rep 2017 05 24;7(1):2380. Epub 2017 May 24.

Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103, Leipzig, Germany.

Cyclooxygenase-2 catalyses the biosynthesis of prostaglandins from arachidonic acid but also the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. Previous studies identified PG-Gs as signalling molecules involved in inflammation. Thus, the glyceryl ester of prostaglandin E, PGE-G, mobilizes Ca and activates protein kinase C and ERK, suggesting the involvement of a G protein-coupled receptor (GPCR). To identify the endogenous receptor for PGE-G, we performed a subtractive screening approach where mRNA from PGE-G response-positive and -negative cell lines was subjected to transcriptome-wide RNA sequencing analysis. We found several GPCRs that are only expressed in the PGE-G responder cell lines. Using a set of functional readouts in heterologous and endogenous expression systems, we identified the UDP receptor P2Y as the specific target of PGE-G. We show that PGE-G and UDP are both agonists at P2Y, but they activate the receptor with extremely different EC values of ~1 pM and ~50 nM, respectively. The identification of the PGE-G/P2Y pair uncovers the signalling mode of PG-Gs as previously under-appreciated products of cyclooxygenase-2.
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http://dx.doi.org/10.1038/s41598-017-02414-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443783PMC
May 2017

Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

Biol Psychiatry 2017 Oct 15;82(7):488-499. Epub 2017 Mar 15.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address:

Background: Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood.

Methods: We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice.

Results: Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation.

Conclusions: Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.
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http://dx.doi.org/10.1016/j.biopsych.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585044PMC
October 2017

Accelerating Precision Drug Development and Drug Repurposing by Leveraging Human Genetics.

Assay Drug Dev Technol 2017 Apr 5;15(3):113-119. Epub 2017 Apr 5.

4 Department of Biomedical Informatics, Vanderbilt University School of Medicine , Nashville, Tennessee.

The potential impact of using human genetic data linked to longitudinal electronic medical records on drug development is extraordinary; however, the practical application of these data necessitates some organizational innovations. Vanderbilt has created resources such as an easily queried database of >2.6 million de-identified electronic health records linked to BioVU, which is a DNA biobank with more than 230,000 unique samples. To ensure these data are used to maximally benefit and accelerate both de novo drug discovery and drug repurposing efforts, we created the Accelerating Drug Development and Repurposing Incubator, a multidisciplinary think tank of experts in various therapeutic areas within both basic and clinical science as well as experts in legal, business, and other operational domains. The Incubator supports a diverse pipeline of drug indication finding projects, leveraging the natural experiment of human genetics.
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http://dx.doi.org/10.1089/adt.2016.772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399743PMC
April 2017

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

Nat Commun 2017 03 28;8:14782. Epub 2017 Mar 28.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.
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http://dx.doi.org/10.1038/ncomms14782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379055PMC
March 2017
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