Johns Hopkins University

Other

Gpi Nil Holdings Inc.

Burroughs Wellcome Co.

The University of Chicago

Memorial Sloan Kettering Cancer Center

The United States of America

Nelson Research & Development Company

University of Vermont College of Medicine

Solomon H Snyder

Ted M Dawson

Joseph P Steiner

Gregory S Hamilton

Gabriele V Ronnett

Samie R Jaffrey

Lynda D Hester

Valina L Dawson

Paul J Tempst

Hediye Erdjument-Bromage

Randall R Reed

Jonathan Pevsner

Christopher D Ferris

David S Bredt

Xiao-Jiang Li

Robert F Bruns

Mary Lui

John W Daly

W Ernest Lyons

David M Sabatini

Edwin B George

Sangwon Kim

Craig B Warren

Paul F Worley

Martial Ruat

Xinzhong Dong

Arthur L Burnett

Anthony A Lanahan

Edythe D London

Gregory Stein

George R Uhl

Charles J Lowenstein

Richard J Traystman

Jie Zhang

Nanduri R Prabhakar

Randen Patterson

Damian Brett Van Rossum

Xintong Dong

Jeffrey S Nye

Christopher A Ross

Shi-Hua Li

Alan H Sharp

Robert J Gould

Seth Blackshaw

Felice F Borisy

Anne M Cunningham

Mary K Conrad

Mathew M Lo

Tian Y Tsong

Thomas S Chang

Andrew Pieper

Moataz M Gadalla

Gary Pace

Nilkantha Sen

Risheng Xu

Alex Huang

Cory Teuscher

Anutosh Chakraborty

Michael Koldobskiy

Katherine Sixt

Krishna Juluri

Asif K Mustafa

Chirag Vasavda

James Meixiong

Yingying Cheng

Nathachit Limjunyawong

Crystal C Watkins

Patricia D Hurn

Kenji Sampei

Allen S Mandir

Jun Bao

Mikael J Eliasson

Loren Walensky

Chirag Vasada

The present invention relates to cells and methods for detecting compounds that affect G protein coupled receptor mediated conditions. The invention also relates to methods for treating adverse drug reactions, autoimmune disorders, and pruritus.

Method for treating a chronic itch condition by administering small molecule MrgprX4 antagonists

Described herein are methods for modulation of the activity of the carotid body that afford therapeutic benefit for sleep-related breathing disorders and related conditions.

Methods for treatment of sleep-related breathing disorders

The present invention relates to the field of drug abuse. More specifically, the present invention provides methods and compositions for treating drug abuse by preventing GAPDH nitrosylation. In one specific embodiment, a method for preventing the stimulant and neurotoxic effects of cocaine comprises the step of administering a compound that prevents the nitrosylation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by nitric oxide (NO). In another embodiment, a method for preventing the stimulant and neurotoxic effects of cocaine comprises the step of administering a compound that prevents the binding of GAPDH to Siah.

Treatment of drug abuse by preventing GAPDH nitrosylation

The atypical antipsychotic drugs (AAPDs) have markedly enhanced the treatment of schizophrenias but their use has been hindered by the major weight gain elicited by some AAPDs. We found that orexigenic AAPDs potently and selectively activate hypothalamic AMP kinase (AMPK), an action abolished in mice with deletion of histamine H1 receptors. These findings afford a means of developing better therapeutic agents and provide insight into the hypothalamic regulation of food intake.

Methods for predicting psychotropic drugs which elicit weight gain

Anti-cancer drugs are identified by screening for agents and compounds which inhibit the binding of HSP90 and IP6K2. In vitro and in vivo assays can be used. Any phenomenon associated with the binding or inhibition can be monitored, including cell death, subcellular localization, catalytic activity of IP6K2, and IP7 formation.

Regulation of cell survival by HSP90 and IP6K2

Cyclooxygenase (COX2) and inducible nitric oxide synthase (iNOS) are two major inflammatory mediators. Inducible NOS specifically binds to COX2 and S-nitrosylates it, enhancing COX2 catalytic activity. Selectively disrupting iNOS&#x2014;COX2 binding prevents NO-mediated activation of COX2. The synergistic molecular interaction between two inflammatory systems permits assays for developing anti-inflammatory drugs.

Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2

Many of the effects of nitric oxide are mediated by the direct modification of cysteine residues resulting in an adduct called a nitrosothiol. A method to detect proteins which contain nitrosothiols involves several steps. Nitrosylated cysteines are converted to tagged cysteines. Tagged proteins can then be detected, for example, by immunoblotting and/or can be purified by affinity chromatography. The method is applicable to the detection of S-nitrosylated proteins in cell lysates following in vitro S-nitrosylation, as well as to the detection of endogenous S-nitrosothiols in selected protein substrates.

Method for assaying protein nitrosylation

Disclosed are methods for preventing or treating a gastrointestinal (GI) disorder in a mammal such as a human patient. In one embodiment, the methods include administering to the mammal a therapeutically effective amount of a compound that modulates a nitric oxide (NO) signaling pathway, particularly in GI neurons. Methods of the invention are particularly useful for the treatment (including prophylactic treatment) of diabetic gastropathies and other GI disorders.

Methods for prevention and treatment of gastrointestinal disorders

This invention relates to the method of using neurotrophic pipecolic acid derivative compounds having an affinity for FKBP-type immunophilins as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity to stimulate or promote neuronal growth or regeneration.

Inhibitors of rotamase enzyme activity

A protein complex containing 245 kDa and 35 kDa components, designated RAFT1 and RAFT2 (for apamycin nd KBP12 arget) interacts with FKBP12 in a rapamycin-dependent manner. This interaction has the pharmacological characteristics expected from the observed in vivo effects of rapamycin: it occurs at low nanomolar concentrations of rapamycin and is competed by excess FK506. Sequences (330 amino acids total) of tryptic peptides derived from the affinity purified 245 kDa RAFT1 reveals striking homologies to the predicted products of the yeast TOR genes, which were originally identified by mutations that confer rapamycin resistance in yeast. A RAFT1 cDNA was obtained and found to encode a 289 kDa protein (2550 amino acids) that is 43% and 39% identical to TOR2 and TOR1, respectively.

Mammalian proteins that bind to FKBP12 in a rapamycin-dependent fashion

A protein complex containing 245 kDa and 35 kDa components, designated RAFT1 and RAFT2 (for Rapamycin And FKBP12 Target) interacts with FKBP12 in a rapamycin-dependent manner. This interaction has the pharmacological characteristics expected from the observed in vivo effects of rapamycin: it occurs at low nanomolar concentrations of rapamycin and is competed by excess FK506. Sequences (330 amino acids total) of tryptic peptides derived from the affinity purified 245 kDa RAFT1 reveals striking homologies to the predicted products of the yeast TOR genes, which were originally identified by mutations that confer rapamycin resistance in yeast. A RAFT1 cDNA was obtained and found to encode a 289 kDa protein (2550 amino acids) that is 43% and 39% identical to TOR2 and TOR1, respectively.

This invention relates to the method of using neurotrophic cyclophilin inhibitor compounds having an affinity for cyclophilin-type immunophilins as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity.

Methods of using inhibitors of cyclophilin rotamase activity to affect neurological activity

Immunophilin-binding agents inhibit the phosphatase calcineurin, leading to the increased phosphorylation of certain brain proteins, including nitric oxide synthase. The increased levels of phosphorylation of nitric oxide synthase inhibits the enzymatic production of nitric oxide. Thus the neurotoxic effects of glutamate, which are ordinarily the result of vascular strokes and other neurodegenerative diseases, are minimized, because the neurotoxic effects are at least partially mediated by nitric oxide. Thus immunophilin-binding drugs can be used therapeutically in the treatment of vascular stroke and neurodegenerative disorders such as Alzheimer's disease and Huntington's disease.

Immunophilin-binding agents prevent glutamate neurotoxicity associated with vascular stroke and neurodegenerative diseases

Neutral tissue damage resulting for ischemia and reperfusion injury or neurodegenerative diseases can be prevented by administering therapeutically effective amounts of certain selective inhibitors of poly(ADP-ribose)polymerase. The inhibitors can be administered intravenously, intraperitoneally, intramuscularly, intraventricularly, or orally. They can be administered as a capsule or tablet containing single or divided dose. Alternatively, the inhibitors can be administered as a sterile solution, suspension or emulsion.

Method of using selective parp inhibitors to prevent or treat neurotoxicity

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Baltimore, MD, United States of America

Solomon H Snyder