Modulation of Sarcoplasmic Reticulum Calcium Release

肌浆网钙释放的调节

基本信息

批准号：
7942850
负责人：
SUSAN L HAMILTON
金额：
$ 46.03万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-08-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7942850
关键词：
Adult Affinity Amino Acids Behavior Binding Binding Sites Calcineurin Calcium Carboxylic Acids Cardiovascular Diseases Coupling Depressed mood Development Dose Electroporation Embryo FK506 Failure Fatigue Fiber Growth Growth Factor Homeostasis Immunofluorescence Immunologic Immunophilins Immunosuppression Immunosuppressive Agents Injury Laboratories Location Lung diseases Measurement Mechanics Medical Membrane Mus Muscle Muscle Fibers Muscle function Mutate Mutation Myopathy Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Probability Production Property Proteins Protocols documentation Recovery Rehabilitation therapy Relative (related person)Research Respiratory Diaphragm Respiratory Failure Role RyR1 RyR3 Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Sarcoplasmic Reticulum Signal Transduction Sirolimus Skeletal Muscle Skeletal muscle injury Staining method Stains Tacrolimus Binding Protein 1A Tacrolimus Binding Proteins Testing Time Transforming Growth Factors Triad Acrylic Resin Ventilator Vesicle Weaning Work calcineurin phosphatase design human FRAP1 protein improved in vivo mutant myostatin novel novel therapeutic intervention prevent public health relevance receptor response sensor voltage

项目摘要

DESCRIPTION (provided by applicant): FKBP12 is a small immunophilin that binds with high affinity to sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors, RyRs) and transforming growth factor 21 receptors (T2I RI). In this application we are going to test the hypothesis that the gain of E-C coupling is regulated in a biphasic manner by FKBP concentration. Specifically we will: 1) Demonstrate that FKBP12 binding to RyR1 controls the gain of E-C coupling in a biphasic manner, thereby, modulating Ca2+ stores, force production, fatigue, and recovery from injury; 2) Evaluate the ability T2RI activation to increase the gain of E-C coupling via FKBP12; 3) Evaluate the ability of drugs that decrease FKBP12 binding to RyR1 to slow the development of fatigue and enhance recovery from injury and 4) Identify the amino acids on RyR1 that contribute to FKBP12 binding. The research described in this application will clarify the role of FKBP12 in skeletal muscle function and lay the groundwork for the development of new therapeutic interventions to slow diaphragm fatigue and enhance recovery from injury. PUBLIC HEALTH RELEVANCE: The research in this application will investigate the role of small immunophilins (FKBPs) in muscle Ca2+ homeostasis, fatigue, and recovery from injury. Diaphragm fatigue is a serious medical problem that contributes to respiratory failure in patients with skeletal muscle, cardiovascular and pulmonary diseases and to failure to wean patients from ventilators. Also, the rate of recovery of skeletal muscle from injury has profound effects on rehabilitation.

描述（由申请人提供）：FKBP12是一种小型免疫蛋白，与肌质网Ca2+释放通道（Ryanodine受体，RYRS）和转化生长因子21受体（T2I RI）结合。在此应用中，我们将检验以下假设：E-C耦合的增益通过FKBP浓度以双相性方式调节。具体而言，我们将：1）证明FKBP12与RYR1结合以双相方式控制E-C耦合的增益，从而调节CA2+商店，造成损伤的ca2+商店，力产生，疲劳和恢复； 2）评估通过FKBP12增加E-C耦合增益的能力T2RI激活； 3）评估降低FKBP12与RYR1结合减慢疲劳发展并增强损伤恢复的药物的能力，4）确定RYR1上有助于FKBP12结合的RyR1上的氨基酸。本应用中描述的研究将阐明FKBP12在骨骼肌肉功能中的作用，并为开发新的治疗干预措施开发以减慢隔膜疲劳并增强损伤恢复的基础。公共卫生相关性：本申请中的研究将调查小型免疫蛋白（FKBP）在肌肉Ca2+稳态，疲劳和受伤中恢复中的作用。隔膜疲劳是一个严重的医学问题，导致骨骼肌，心血管和肺部疾病患者的呼吸道衰竭以及未能从呼吸机中解除患者的呼吸衰竭。同样，骨骼肌从损伤中恢复的速度对康复产生了深远的影响。