FUNCTIONAL EFFECTS OF CARDIOMYOPATHIC MYOSIN MUTATIONS

说明： 该项目旨在定义由以下因素引起的功能缺陷 导致肥厚型心肌病(HCM)的心肌肌球蛋白突变。 将在人类缓慢的骨骼肌纤维上进行实验 来自正常和肥厚型心肌炎患者的活组织检查，以及 转人心肌肌球蛋白重链基因的体外培养的鹌鹑肌管 锁链。中心假设是HCM中的突变肌球蛋白具有 功能受损。兰克福德博士将利用分子技术创造 突变的人肌球蛋白重链结构将在 鹌鹑肌源性细胞培养。一些突变的肌球蛋白将是 构建的将类似于发现的自然产生的突变肌球蛋白 在肥厚型心肌炎患者中，其他人会有不同的突变。 力学研究将在分离的肌管上进行。 培养使突变肌球蛋白的性能得以量化。 申请者还将研究人类骨骼肌活组织检查。 胡志明市。这些对这两个不同系统的研究将允许 增加了对肌动蛋白产生力量的过程的理解- 肌球蛋白相互作用，以及肌球蛋白的结构/功能关系 肌球蛋白重链。这些研究将在 李·斯威尼博士是一位助理教授，他咨询了斯威尼博士。 朱迪思·L·斯温，这一领域的国际公认的领导者 肌肉生物学。

DESCRIPTION: This project is aimed at defining the functional deficits resulting from cardiac myosin mutations that cause hypertrophic cardiomyopathy (HCM). Experiments will be carried out on human slow skeletal muscle fibers obtained from biopsies from normal and HCM patients, as well as on cultured quail myotubes transfected with human cardiac myosin heavy chains. The central hypothesis is that the mutant myosin in HCM has impaired function. Dr. Lankford will use molecular techniques to create mutant human myosin heavy chain constructs that will be expressed in quail myogenic cell cultures. Some of the mutant myosins to be constructed will resemble the naturally occurring mutant myosins found in patients with HCM, while others will have different mutations. Mechanical studies will be performed on isolated myotubes from these cultures to allow quantification of the performance of mutated myosin. The applicant will also study skeletal muscle biopsies from humans with HCM. These studies in these two different systems will allow an increased understanding of the process of force generation by actin- myosin interaction, and the structure/function relationship in the myosin heavy chain. The studies will be performed in the laboratory of Dr. Lee Sweeney, an assistant professor, with consultation with Dr. Judith L. Swain, an internationally recognized leader in the field of muscle biology.