SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

描述：(改编自申请者的摘要)这方面 该项目致力于通过提高特异性来解决MH的遗传学问题 活检肌肉收缩试验对MH表型的敏感性。 该项目将确定是否可以从 病人被放置在去皮溶液中，并被运往检测中心 在那里，将测试单一纤维，而不是大束纤维。数字 中使用的6到9束中的一束中包含的单纤维 目前的测试约为200次，这说明了有多少材料可用 用于单光纤测试。此外，带皮的纤维可以存储为 几个星期，每个纤维都可以重新测试几次，而无需 对回应的重大改变。该项目的另一个方面将是 在50%的家庭中寻找导致MH的突变 与19号染色体没有关联。FKBP12蛋白与19号染色体紧密结合 并调节RYR1钙释放通道(CRC)。当FKBP12为 从RYR1分离出来，CRC对咖啡因诱导变得更敏感 频道开通。FKBP12对CRC的这些影响使其成为主要嫌疑人 用于MH病因学。申请者将筛查FKBP12突变 肌挛缩症患者的表型并测试其功能效果 重组突变型FKBP12蛋白替代天然FKBP12的研究 单皮纤维肌挛缩对肌浆钙释放的影响 网状膜小泡。

DESCRIPTION: (Adapted from the applicant's abstract) One aspect of this project focuses on resolving the genetics of MH by improving the specificity and sensitivity of MH phenotyping by contracture testing of biopsied muscle. The project will determine if smaller amounts of muscle can be taken from the patient, placed in a skinning solution and shipped to a testing center where single fibers, rather than large bundles, will be tested. The number of single fibers contained in just one of the 6 to 9 fascicles used in current testing is about 200, illustrating how much material is available for single fiber testing. In addition, skinned fibers can be stored for several weeks, and each fiber can be retested several times without significant change to responses. The other aspect of the project will search for a mutation that causes MH in the 50 percent of families in which there is no linkage to chromosome 19. The FKBP12 protein binds avidly to and modulates the RYR1 calcium release channel (CRC). When FKBP12 is dissociated from RYR1, the CRC becomes more sensitive to caffeine-induced channel opening. These effects of FKBP12 on the CRC make it a prime suspect for MH etiology. The applicant will screen for FKBP12 mutations in contracture phenotyped patients and test the functional effects of replacement of native FKBP12 with recombinant, mutant FKBP12 proteins on contracture in single skinned fibers and on calcium release in sarcoplasmic reticulum membrane vesicles.