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Identification of Novel Drug Targets For Use in Preventing Deafness Caused by NF2

鉴定用于预防 NF2 引起的耳聋的新药物靶点

基本信息

批准号：
8278031
负责人：
CRISTINA Maria FERNANDEZ-VALLE
金额：
$ 28.81万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8278031
关键词：
Acoustic Nerve Acoustic Neuroma Actins Adult Apoptosis Auditory Brain Stem Implants Autocrine Communication Axon Basal lamina Binding Brain Stem Cancer Biology Cell Death Cell Shape Cell membrane Cell physiology Cell-Cell Adhesion Cells Cellular Morphology Complete Hearing Loss Complex Cues Cyclic AMP-Dependent Protein Kinases Cytokinesis Cytoskeleton Defect Development Disease Drug Delivery Systems Effectiveness Equilibrium Excision Facial paralysis Genes Goals Growth Hearing Human In Vitro Individual Integrins Investigation LIM Domain Kinase 1 Laminin Life Ligands Link Malignant Neoplasms Measures Membrane Membrane Proteins Mitotic spindle Molecular Monitor Morphology Mus Mutate Mutation Nerve Neuregulins Neurilemmoma Neurofibromatosis 2 Neurofibromin 2 Neurons Operative Surgical Procedures Orphan Outcome Pathogenesis Pathway interactions Patients Peptides Pharmaceutical Preparations Pharmacological Treatment Phenotype Phosphorylation Plasmids Play Positioning Attribute Process Proteins Rattus Reagent Regulation Reporting Research Personnel Risk Role Schwann Cells Serine Shapes Signal Pathway Signal Transduction Signaling Protein Site Spinal Ganglia Stream Subfamily lentivirinae Symptoms Teenagers Testing Therapeutic Tumor Suppressor Proteins Virus Work bilateral acoustic schwannoma bilateral vestibular Schwannoma cell motility cofilin cofilin 2 deafness density effective therapy experience extracellular genetic regulatory protein hearing impairment in vitro Model irradiation novel novel therapeutics p21 activated kinase paxillin polymerization prevent receptor repaired response success tumor tumor growth

项目摘要

PROJECT SUMMARY Neurofibromatosis type 2 (NF2) is a tumor disorder characterized by development of bilateral vestibular schwannomas also called acoustic neuromas. 98% of all NF2 patients experience partial to complete loss of hearing. Treatment for NF2 is balanced between monitoring tumor growth and the slow but progressive loss of hearing with surgical removal of larger tumors impinging on brainstem function and complete and permanent deafness. Cochlear and auditory brainstem implants have been used to partially restore hearing in a subset of patients with varying success. Therapeutics that slow or reverse tumor growth whilst maintaining hearing are currently lacking. This proposal tests the hypothesis that correcting the cytoskeletal defects in supernumerary schwannoma cells lacking function of the nf2 gene product, schwannomin/merlin, will allow these cells to interact with axons and receive cues promoting their differentiation and/or apoptosis. Identifying proteins that directly bind actin and regulate Schwann cell morphology is of the utmost importance. These proteins can serve as targets for drugs that will repair actin dynamics in schwannoma cells and restore axonal contact. Alternatively, drugs that modify actin regulatory proteins could promote cell death as a result of failed cytokinesis and mitotic spindle organization. One function of schwanomin/merlin is to inhibit Cdc42/Rac activation of p21 activated kinase (PAK). We will investigate LIM kinase (LIMK) and cofilin, terminal targets in a PAK signaling pathway. LIMK is a substrate for PAK, thus its activity is predicted to be high in schwannomas. Cofilin is a ubiquitously expressed actin-binding factor that depolymerizes f-actin and creates nucleation sites for new actin polymerization. Cofilin's function is inhibited by phosphorylation on serine-3 by LIMK. Our preliminary studies demonstrate that LIMK and cofilin modulate actin dynamics and function in Schwann cells. Moreover, our results suggest that LIMK and cofilin act down-stream of Schwannomin/merlin. We propose studies to: 1) identify the role of these proteins in controlling actin polymerization and cellular function in normal rat Schwann cells, 2) establish an in vitro model for NF2 using nf2ex2deleted mouse SCs to determine if inactivation of schwannomin/merlin leads to de-regulation of LIMK and cofilin activity and loss of SC function, and 3) determine if modulators of LIMK and cofilin restore the morphology and function of nf2ex2deleted SCs. These studies are initial steps in validating LIMK and/or cofilin as drug targets for development of an effective treatment for NF2 aimed at preserving hearing.

项目总结