1985 — 2017 |
Snyder, Solomon H |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Drug Abuse Research Center @ Johns Hopkins University
Areas of drug abuse related research being explored: 1. Differentiating - and -receptors; 2. Characterization of enkephalin innervation from caudate to globus pallidus; 3. Adenosine receptors; 4. Peptide disposition; bradykinin and cholecystokinin; 5. Studies of benzodiazepine receptors; 6. Studies on opiate receptors; a. lesion studies localize receptors to specific cell types; b. anatomical mapping of subtypes of receptors; c. opioid receptors undergo axonal flow. 7. Benzodiazepine receptors and their subtypes, beta-adrenergic receptors and serotonin receptors mapped in the brain; Characterization of neocortical cholinergic pathways.
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1985 — 2019 |
Snyder, Solomon H. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Neurochemical Actions of Psychotropic Drugs @ Johns Hopkins University
DESCRIPTION (provided by applicant): Our research, supported by this grant over the years, has focused on identifying and characterizing novel neural messenger molecules and their roles in psychotropic drug actions. We propose new studies based on recent advances in this area involving, in particular, gasotransmitters and D-amino acids. Based on our earlier work on NO and CO, we have recently identified hydrogen sulfide (H2S) as a notable signaling molecule. We established its biosynthesis by cystathionine-gamma-lyase (CSE) and cystathionine- beta-synthase (CBS) by demonstrating its depletion with CSE and CBS knockout. We showed that H2S signals by sulfhydrating cysteines in target proteins, analogous to NO acting by nitrosylation. We will map CBS/CSE and their catalytic activity via a novel histochemical stain for H2S generation from cysteine. We will characterize new sulfhydrated targets. Based on our findings regarding CSE's transcriptional induction, we will elucidate the enzyme's turnover under diverse conditions. Recently we discovered a profound depletion of CSE in Huntington's Disease (HD) reflecting mutant huntingtin affecting the CSE transcription factor SP1. Pathophysiologic relevance was evident in the alleviation of the HD phenotype by rescue in cultures and intact mice by cysteine supplementation. We will further characterize cysteine/H2S dynamics in HD mice and neural cultures. The cysteine depletion may also account for the inanition of HD patients. Accordingly, we will also investigate the regulation by CSE of adiposity. We established D-serine as an endogenous agonist for glutamate-NMDA receptors, identifying, cloning and characterizing its biosynthetic enzyme serine racemase (SR). Recently, we discovered that SR can link AMPA and NMDA glutamate transmission. SR binds the AMPA receptor accessory protein stargazin leading to membrane association and SR inhibition. SR also binds PSD-95 from which it is dissociated by NMDA treatment. We will elucidate the physiologic significance of SR in an apparent cross-talk between AMPA and NMDA receptor systems. We recently identified substantial levels of D-cysteine in mammalian brain and other tissues. We have developed a novel sensitive and specific assay for tissue D-cysteine. We will monitor D-cysteine levels in diverse tissues under varying circumstances. We will seek biosynthetic mechanisms for D-cysteine via known or hitherto unidentified enzymes.
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1985 — 2009 |
Snyder, Solomon H |
K05Activity Code Description: For the support of a research scientist qualified to pursue independent research which would extend the research program of the sponsoring institution, or to direct an essential part of this research program. |
Neurotransmitter Receptors @ Johns Hopkins University
My aims for research during the coming five years include a number of different projects. One has to do with the characterization of enkephalin convertase, a carboxypeptidase which appears to be associated with the biosynthesis of enkephalin. We will try to measure the turnover of the enzyme and evaluate in detail its localization. Another project relates to angiotensin converting enzyme which can be labeled with the inhibitor H-3-captopril. We propose to attempt to identify what seems to be a novel neuropeptide which is the endoyenous substrate for this enzyme. We propose to localize endogenous adenosine and ascertain its possible neutrotransmitter role. We will continue studies of calcium antagonist receptors and their relationship to calcium flux in neurons. We will characterize biogenic amine uptake sites with a variety of ligands. We propose studies to further elucidate the function of sigma receptors which are associated with the psychotomimetic effects of opiates. We propose detailed investigations of phorbol ester receptors to clarify their relationship to protein kinase C in neuronal function. We will also evaluate the relationship of the receptor interactions fo neutoxin MPTP with monamine oxiuase.
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1987 |
Snyder, Solomon H |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Catecholamine Symposium: Mental Health Aspects @ Johns Hopkins University
Funding is requested for partial travel support of participants to the Seventh International Catecholamine Symposium. Catecholamines are of great importance as mediators of the actions of numerous drugs in psychiatry, especially antidepressants and antischizophrenic agents. The last few years has witnessed major advances in understanding of basic aspects of catecholamines in brain function and their relevance for understanding how psychotropic drugs act and developing new, more effective therapuetic agents. Catecholamines are also relevant to several neurological conditions. For instance, L-dopa and other therapeutic agents in Parkinson's disease act via catecholamines. MPTP, which produces in humans and animals a model of Parkinsons disease, acts by destruction of dopamine neurons. Catecholamines play a major role in drug abuse research. For instance, amphetamines and cocaine depend upon catecholamines for their psychoactive effects. Catecholamines are crucial in numerous aspects of cardiovascular functions. For instance, major drugs used in treating hypertension and angina act via catecholamines. The symposium will take place in Jerusalem of June 14-19, 1987 and involve 600-800 participants. The newest advances in cateholamine research will be presented in numerous fields of inquiry ranging from fundamental molecular biology to clinical investigations of different disease processes. The meeting format will embrace plenary lectures, symposia, short oral presentations and posters.
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1990 |
Snyder, Solomon H |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Degeneration of Locus Coeruleus Neurons @ Johns Hopkins University
The locus coeruleus (LC) is the largest noradrenergic (NA) cell group in the central nervous system. In the human LC, there is extensive cell loss with normal aging. Premature loss of LC neurons is particularly dramatic in Parkinson;s disease and in Alzheimer's disease. The mechanisms underlying the LC neuron death are not known. We have recently found that a single systemic injection of the NA neurotoxin DSP-4 into rats causes rapid and profound depletion of norepinephrine (NE) from LC axons. This depletion of neurotransmitter is followed by degeneration of LC axons within two weeks and by loss of more than 50% of the cells in the LC 6 and 12 months after DSP-4 administration. Regeneration of NA axons occurs in forebrain regions previously depleted by DSP-4 but not in brainstem regions, cerebellum and spinal cord. The goals of this application are to characterize the relationship between the DSP-4 induced depletion of NE, NA axon degeneration and NA neuron loss, and to explore the mechanisms that underlie DSP-4 induced LC neuron death. We propose three sets of experiments: (1) To describe the onset and progression of NA neuron loss, we will count cells in all NA subgroups between 1 and 18 months after DSP-4 treatment. For identification of NA neurons we will use dopamine-B-hydroxylase degeneration, NA axon regeneration and LC neuron loss, we will label specific subsets into either frontal cortex, thalamus, cerebellum or spinal cord. Two weeks thereafter, rats will be injected with either DSP-4 or saline and the fate of retrogradely labeled NA neurons will be determined 6 months later by examining a tight linkage between the DSP-4 induced NE depletion and LC axon degeneration, we propose that NE itself and radicals formed during oxidative deamination of NE play role in the neurotoxicity of DSP-4. We will test this hypothesis by determining whether the rate and extent of NA axon degeneration and NA neuron loss after DSP-4 can be influenced by pretreatment with drugs that alter intracellular levels of NE and by drugs that reduce the levels of glutathione in the central nervous system.
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1994 |
Snyder, Solomon H |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Prohormone Cleaving Enzymes in Brain and Pituitary @ Johns Hopkins University |
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1997 — 2001 |
Snyder, Solomon H |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Nitric Oxide, Heme Oxygenase 2, and Novel Regulatory Proteins of Pineal Gland @ Johns Hopkins University
heme oxygenase; nitric oxide; adenosinetriphosphatase; neuropharmacology; acyltransferase; serotonin; pineal body; cyclic GMP; copper; drug abuse; blood vessels; bilirubin; biological signal transduction; carbon monoxide; citrulline; neurotoxins; neurotransmitters; melatonin; tissue /cell culture; laboratory rat; laboratory mouse; guinea pigs; in situ hybridization; immunocytochemistry;
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2007 — 2021 |
Snyder, Solomon H. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administrative Core @ Johns Hopkins University
Administrative Core The administrative core of our center integrates the various elements enhancing the multidisciplinary, synergistic integration of the central theme "Dynamics of signaling by molecular messengers relevant to drugs of abuse." It coordinates research enabling a focus in the areas of NIDA's mission. Because of the core, our Center is able to serve as a national resource and at Hopkins to facilitate the integration of research activity and sharing of resources as well as providing adequate and appropriate facilities for administrative activities. The shared facilities are located in the area of the core and funded by the core. The Center director is part of the core enabling the individual investigators to carry out their responsibilities effectively. The core also enables the Center to carry out its responsibilities as regards mentoring and career development.
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2007 — 2011 |
Snyder, Solomon H. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Molecular Messengers That Underlie Neurotoxic and Other Actions of Drugs of Abuse @ Johns Hopkins University
Our proposal investigates molecular messengers that underlie neurotoxic and other actions of drugs of abuse. Specific areas covered in the research plan are neurotoxic influences of nitric oxide signaling, glyceraldehyde-3 -phosphate dehydrogenase and heme oxygenase/biliverdin reductase. Additionally, we will continue studies of D-aspartate as a neuromodulator and mediators of cell stress such as p53, areas which, for the sake of brevity, are detailed separately in the Progress Report.
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2012 — 2017 |
Snyder, Solomon H. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Research Project 1 @ Johns Hopkins University
Research focuses on molecular messenger systems characterized in the Snyder laboratory which are substrates for actions of drugs of abuse. One involves a signaling cascade linking nitric oxide (NO), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the ubiquitin E3-ligase Siah-1 and nuclear targets. A second deals with inositol hexakisphosphate kinase-2 (IPK6K2) in cell death and neurotoxicity, while a third addresses inositol polyphosphate multikinase (IPMK) and neural function. The NO-GAPDH-Siahl pathway was discovered as a cell death signaling system acting via nuclear p53. Recent work reveals a physiologic role wherein nitrosylated GAPDH, responding to neuronal growth factors, via Siah-1, degrades the histone methylating enzyme SUV39H1 leading to histone acetylation, gene transcription and dendritic outgrowth. Cocaine, in behavioral stimulant doses, activates this pathway. We will elucidate this pathway. IP6K2, a mediator of apoptosis, acts via p53. We are assessing how it distinguishes cell arrest/cell death via influences upon DNA protein kinase to activate p53. Its role in cocaine and MPTP actions is being investigated. IPMK is an inositol phosphate kinase and a PI3-kinase. We recently discovered that it is physiologically nitrosylated and acetylated, then binds to CBP and CREB, apparently activating CREB genetic programs. Cocaine administration activates IPMK nitrosylation/acetylation. We will explore its neural functions using newly generated IPMK knockout mice. We recentiy discovered that IPMK binds the small G-protein Rheb, known to activate mTOR. We previously showed that IPMK binds and stabilizes mTOR. We will investigate whether IPMK/Rheb coordinately regulate mTOR signaling in the brain in response to abusable drugs.
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2014 — 2017 |
Snyder, Solomon H. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Gasotransmitters and Plasticity At Teh Excitatory Synapse @ Johns Hopkins University
Glutamate-AMPA receptors are the key mediators of excitatory transmission of which GluA1 is a major subtype. GluA1's conductance is critically determined by phosphorylation at serine-831. We recently discovered that nitric oxide (NO) nitrosylates GluA1 at a specific cysteine, C875. and that this nitrosylation determines S831 phosphorylation. We plan to elucidate mechanisms underlying this important mode of regulation. We will also explore the impact of hydrogen sulfide (H2S) modifying, via sulfhydration, C875 in presumed reciprocity with nitrosylation. We earlier showed that nitrosylation of stargazin, a major auxiliary protein of AMPA receptors, determines GluA1 conductance. We will explore regulation of this process and how it interfaces with gasotransmitter influences exerted directly upon GluA1.
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2018 — 2021 |
Snyder, Solomon H. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Novel Molecular Mechanisms of Abusable Drugs @ Johns Hopkins University
Project Summary ? Snyder Project Our laboratory has long focused on molecular signaling systems in the brain that underlie actions of psychotropic drugs, especially abusable agents. The present proposal addresses two areas of current interest. Cocaine has long been known to impair monoamine transport with modest potency. We recently discovered a very high affinity cocaine `receptor.' As little as 0.1 nM cocaine induces autophagy in cortical cultures, thousands of times more potent than other actions of the drug. We identified BASP-1 protein as the apparent cocaine target. We propose studies to elucidate cocaine-BASP-1 links and their relevance to psychoactivity of cocaine. In a second project, we will explore how ketamine elicits its antidepressant actions via mTOR. We recently established a relevant pathway wherein NMDA signaling triggers NO generation to nitrosylate glyceraldehyde phosphate dehydrogenase (GAPDH) in a complex with the ubiquitin E3-ligase Siah1. In this complex, Siah1 degrades the small G protein Rheb, a physiologic stimulus for mTOR, thereby leading to diminished mTOR activity. By blocking NMDA receptors, ketamine elicits the reverse process, mTOR enhancement. Utilizing a variety of agents, we propose to explicate this signaling system in an effort to understand psychotomimetic/antidepressant actions of ketamine and, hopefully, lead to more effective/safer therapies.
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2018 — 2021 |
Snyder, Solomon H. |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Targeting Cell Signaling Pathways to Disrupt Drug Abuse @ Johns Hopkins University
Project Summary Drug abuse is an enormous public health problem. Accordingly, there is an urgent need to improve our understanding of the molecular mechanisms underlying drug abuse, as this information is vital to developing effective strategies to combat this disorder. Therefore, the overall goal of the Johns Hopkins Drug Abuse Research Center is to catalyze progress in defining the signaling pathways that mediate actions of drugs of abuse. To help achieve this goal, the Center will focus on three specific aims: 1) to catalyze synergistic interactions among Center laboratories investigating molecular actions of drug abuse, 2) to encourage application of innovative approaches to this field, and 3) to help train leaders in drug abuse research. Each of the Center laboratories will focus on innovative topics of research that will benefit from synergistic interactions with other Center laboratories. The Worley lab will study mechanisms of mTORC1 activation and its role in mediating the reinforcing properties of cocaine. The Dawson lab will study Thorase, a member of the AAA+ ATPase family, that regulates synaptic plasticity. In particular, recent studies indicate that Thorase plays a key role in regulating disassembly of mTORC1 signaling complexes. Thus, these studies are highly synergistic with those of the Worley lab. The Baraban lab will study the role of the microRNA system in dopamine signaling. They have found that mice lacking the translin/trax RNase complex, a key enzyme that mediates degradation of a subset of microRNAs, produces robust alterations in behavioral responses to cocaine. The Snyder lab will pursue two recent discoveries. One project will focus on defining the role of the Rheb/mTOR signaling pathway in mediating behavioral effects of ketamine, which links directly to studies conducted by the Worley and Dawson labs. Furthermore, nitrosylation plays a major role in regulating both Rheb and Thorase, providing another node of synergistic interaction. The second project is based on the unexpected observation that cocaine, at nanomolar concentrations, triggers autophagy, a process intimately linked to mTOR signaling. As cocaine exerts its classic behavioral effects in the micromolar range, these findings suggest that it also affects cellular function via a novel, high affinity ?receptor?. The Snyder lab will build on its identification of a candidate high affinity ?receptor? for cocaine to pursue studies aimed at elucidating its function. The Center will establish a Behavioral Core to conduct self-administration assays in mice. As each laboratory uses genetic manipulations in mice to study cell signaling pathways relevant to cocaine action, the Behavioral Core will be an integral, shared facility critical for evaluating the impact of manipulating these pathways on cocaine's reinforcing properties.
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