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dc.contributorNot Applicableen_US
dc.contributor.authorISACKSON, PAUL J Principal Investigatoren_US
dc.date30-Apr-11en_US
dc.date2009en_US
dc.date.accessioned2011-04-18T21:07:23Zen_US
dc.date.accessioned2011-04-19T18:30:57Z
dc.date.available1-Jul-08en_US
dc.date.available2011-04-18T21:07:23Zen_US
dc.date.available2011-04-19T18:30:57Z
dc.date.issued2011-04-18T21:07:23Zen_US
dc.identifier7629026en_US
dc.identifier5R21AR055704-02en_US
dc.identifier55704en_US
dc.identifier.urihttp://hdl.handle.net/10477/1025
dc.descriptionaged;Aging;Agrin;Amino Acid Substitution;Antibody Formation;Binding (Molecular Function);Biological;Cloning;Complementary DNA;Data;Disease;DNA Resequencing;EGF-Like Domain;Exons;Extracellular Matrix;Future;Genes;Genotype;Goals;Human;interest;Laminin;Ligands;loss of function;Maintenance;member;Messenger RNA;mRNA Expression;mRNA Stability;Muscle;muscle degeneration;Muscular Dystrophies;Myopathy;Natural regeneration;Nervous system structure;Neuromuscular Diseases;notch protein;Notch Signaling Pathway;novel diagnostics;Patients;Pattern;Predisposition;Proteins;Receptor Signaling;Recombinants;regenerative;Relative (related person);RNA Splicing;Role;Signal Pathway;Signal Transduction;Skeletal muscle structure;Specificity;Spinal Cord;Therapeutic;Tissues;tool;Transcript;Transcription Initiation Site;Variant;en_US
dc.descriptionAmount: $ 209220en_US
dc.description.abstractDESCRIPTION (provided by applicant): The proposed study would characterize a newly identified gene, narexin on chr6, which contains domains most similar in sequence to Notch ligands and to agrin. Both of these molecules have critical roles in skeletal muscle formation, maintenance of integrity and regenerative potential. Notch signaling has been implicated in regulating the regeneration of aged muscle tissue. Genetically modified forms of agrin have been shown to have therapeutic potential for some forms of muscular dystrophy. Common polymorphic variations have been identified in the narexin gene associated with severe statin-induced myopathies and this suggests that loss of function sequence variations in this gene may result in increased susceptibility to this disease state. Furthermore, the specific expression of the narexin gene in skeletal muscle and the nervous system suggests it will have novel diagnostic and therapeutic applications to neuromuscular disease and skeletal muscle degeneration during aging. The short term goals of this study are to identify causal sequence variations in the narexin gene responsible for increased susceptibility to statin-induced myopathy and to express recombinant, biologically active forms of the protein product. This will be accomplished by a more detailed genotype analysis of the region of association with tag SNPs identified using data available from the HapMap project to capture genotypic variation in this region. Resequence analysis of narexin exons within the region of association will be performed. Functional sequence variations responsible for the association with statin- induced myopathy could be due to sequence variations resulting in amino acid substitutions, mRNA splicing alterations or effects on mRNA stability. The further characterization of the cDNAs amplifiable from muscle and spinal cord will be crucial to fully understanding the function of this gene product. Recombinant forms of the narexin protein will be expressed for the production of antibodies and functional studies. This will provide tools for the longer-term goals of identifying the biological activities, specific receptors and signaling pathways involved in narexin function.en_US
dc.titleROLE OF NAREXIN IN NEUROMUSCULAR DISEASEen_US
dc.typeNIH Grant Awarden_US


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