Poly(ADP-ribosyl)ation is a post-translational modification that plays a central role in the regulation of cell death and DNA repair. PAR serves as a surrogate marker for poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG), which are being actively pursued as therapeutic targets with several PARP inhibitors already in clinical trials. Central to understanding PAR regulation and PARP/PARG drug discovery would be the availability of sensitive, simple and low-cost assays, which are currently unavailable. Thus this Phase 1 application seeks to develop homogeneous assays for PAR utilizing engineered split-protein reporters. The new pharmacodynamic and cellular assays that are proposed will help advance treatment regimens as well as accelerate the development of PARP and PARG inhibitors in both academia and industry.
Public Health Relevance: Poly (ADP-ribosylation), a post-translational modification of proteins, plays a central role in the repair of single strand breaks caused by environmental and metabolic stress. Poly(ADP-ribose) levels in cells are maintained by the dual action of PARP, which synthesizes PAR;and PARG, which degrades PAR in cells. Hence PAR can be used to report on the activity of both these enzymes. The purpose of our application is to develop low-cost, sensitive, luminescence based poly(ADP-ribose) detection assays for drug discovery.
Thesaurus Terms: Adp Ribosylation;Adp-Ribosyltransferase (Polymerizing);Academia;Adenosine 5'-(Trihydrogen Diphosphate), P'-5-Ester With D-Ribose, Homopolymer;Animals;Antibodies;Apoptosis;Apoptosis Pathway;Assay;Benchmarking;Best Practice Analysis;Binding;Binding (Molecular Function);Binding Proteins;Bioassay;Biologic Assays;Biological Assay;Body Tissues;Cancer Of Breast;Cancerous;Cancers;Cell Communication And Signaling;Cell Cycle Arrest;Cell Death;Cell Death, Programmed;Cell Signaling;Cells;Cellular Assay;Clinical Trials;Clinical Trials, Unspecified;Collection;D-Ribose;Dna Damage;Dna Damage Repair;Dna Injury;Dna Repair;Data;Detection;Development;Diagnostic;Engineering;Engineerings;Enzymes;Evaluation;Exposure To;Goals;Guanidine, N-Methyl-N'-Nitro-N-Nitroso-;High Throughput Assay;Ic50;Inflm;Immunologic, Luciferase;In Situ;Industry;Inflammation;Inhibitory Concentration 50;Intracellular Communication And Signaling;Label;Lead;Libraries;Ligand Binding Protein;Light;Luciferases;Mnng;Malignant Neoplasms;Malignant Tumor;Malignant Tumor Of The Breast;Malignant Neoplasm Of Breast;Measurement;Measures;Mediating;Metabolic;Metabolic Stress;Metastatic Melanoma;Methods;Methylnitronitrosoguanidine;Methylnitrosonitroguanidine;Mission;Molecular Interaction;N-Methyl-N'-Nitro-N-Nitrosoguanidine;Nad+[{..}]poly(Adenosine Diphosphate D-Ribose)-Acceptor Adp-D-Ribosyltransferase;Nitrosomethylnitroguanidine;Nitrosonitromethylguanidine;Nuclear;Organism;Parp Polymerase;Pars;Pb Element;Pharmacodynamics;Phase;Photoradiation;Play;Poly Adp Ribose;Poly Adenosine Diphosphate Ribose;Poly(Adp-Ribose) Synthase;Poly(Adp-Ribose) Transferase;Poly(Adp-Ribose) Polymerases;Poly(Adpr) Polymerase;Poly(Adpribose) Polymerase;Poly-Adpr;Polymerase;Post-Translational Modifications;Post-Translational Protein Processing;Posttranslational Modifications;Product Labeling;Protein Modification;Protein Modification, Post-Translational;Protein Processing, Post-Translational;Protein Processing, Posttranslational;Protein/Amino Acid Biochemistry, Post-Translational Modification;Proteins;Protocols, Treatment;Publishing;Rgm;Regimen;Regulation;Reporter;Reporting;Ribose;Role;Sampling;Signal Transduction;Signal Transduction Systems;Signaling;Single Strand Break Repair;Surrogate Markers;Technology;Time;Tissues;Toxin;Treatment Protocols;Treatment Regimen;Treatment Schedule;Unscheduled Dna Synthesis;Validation;Antibody;Base;Biological Signal Transduction;Clinical Investigation;Combat;Cost;Design;Designing;Drug Development;Drug Discovery;Gene Product;Heavy Metal Pb;Heavy Metal Lead;High Throughput Screening;Inhibitor;Inhibitor /Antagonist;Inhibitor/Antagonist;Library;Living System;Luminescence;Malignancy;Malignant Breast Neoplasm;Necrocytosis;Neoplasm /Cancer;Neoplasm/Cancer;Poly Adp Polymerase;Poly Adp Ribose Glycohydrolase Inhibitor;Poly Adp Ribose Synthetase;Poly Adp-Ribose Glycohydrolase;Poly Adpr Glycohydrolase Inhib;Social Role;Success;Therapeutic Target;Tumor Xenograft
