SKELETAL MUSCLE LESION IN MALIGNANT HYPERTHERMIA

描述：（改编自申请人的摘要）其中一个方面 该项目的重点是通过提高特异性来解决MH的遗传问题。 和敏感性MH表型的挛缩测试活检肌肉。 该项目将确定是否可以从 将病人放入皮肤溶液中，然后运送到测试中心， 其中将测试单根纤维，而不是大的纤维束。 数量 所用的6至9个纤维束中的一个纤维束中含有的单纤维 目前的测试是大约200，说明有多少材料是可用的 用于单根光纤测试。 此外，剥皮的纤维可以储存用于 几个星期，每根纤维可以重新测试几次， 应对措施的重大变化。 该项目的另一个方面将 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蛋白强烈结合于 并调节RYR1钙释放通道（CRC）。 当FKBP 12 与RYR1分离后，CRC对咖啡因诱导的 渠道开放 FKBP 12对CRC的这些作用使其成为主要怀疑对象。 用于MH病因学。 申请方将在以下患者中筛选FKBP12突变： 挛缩表型患者和测试功能的影响， 用重组突变FKBP12蛋白替代天然FKBP12， 肌浆内钙释放的影响 网网膜小泡。

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.