Obscurin & Myofibrils in Cardiac & Skeletal Muscle
暗色素
基本信息
- 批准号:7822220
- 负责人:
- 金额:$ 1.06万
- 依托单位:
- 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:2009-06-01 至 2010-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAdenovirus VectorAdultAffectAffinityAnkyrinsAntibodiesBindingBinding SitesBiochemicalBiological AssayC-terminalCardiacCollaborationsContractile ProteinsCoupledCytoskeletonElementsEpitopesGene ExpressionHandHeadHybridsHypertrophic CardiomyopathyImmunologic TechniquesIndiumIntegral Membrane ProteinLabelLearningLengthLinkMapsMeasurementMembraneMolecular CloningMorphogenesisMorphologyMuscle FibersMuscular DystrophiesMutationMyofibrillogenesisMyofibrilsMyosin ATPasePH DomainPlayProteinsReactionReportingResearch PersonnelRestRoleSarcomeresSarcoplasmic ReticulumSignal TransductionSiteSkeletal MuscleSmall Interfering RNAStriated MusclesStructureSurface Plasmon ResonanceTestingThickThick FilamentThin FilamentTransfectionYeastsconnectinknock-downnebulinobscurinoverexpressionprogramsresearch studyscaffoldskeletaluptake
项目摘要
DESCRIPTION (provided by applicant): In recent years, we have learned a great deal about the assembly of thick and thin filaments in striated muscle, and about the proteins that regulate the release and re-uptake of Ca2+ essential for the contractile cycle. We know much less, however, about the mechanisms that integrate thick and thin filaments into myofibrils, and about the proteins that organize the sarcoplasmic reticulum (SR) and transverse (t-) tubules so regularly around sarcomere. The recent discovery of obscurin offers new ways to address these questions.
Obscurin is an approximately 800 kDa protein with structural homology to titin. It is the only protein of the titin superfamily that is concentrated, at least in part, at the periphery of sarcomeres, primarily around M-lines and Z-disks. Obscurin is composed largely of tandem Ig domains but also has signaling domains and, at its extreme COOH-terminus, a binding site for a small, integral membrane form of ankyrin 1 that is concentrated in the network SR. Given its apparent ability to concentrate at the periphery of the myofibril around M-lines and Z-disks and its high affinity for an integral protein of the SR membrane, obscurin is ideally suited to play key roles in assembling and organizing both the sarcomere and the SR. We propose to test this general hypothesis through 4 specific aims: (1) to learn how obscurin is organized with respect to key structures within sarcomeres; (2) to learn how obscurin binds to elements in the contractile apparatus; (3) to assess the effect on morphogenesis of the myofibrils and associated membranes of altering the activity of obscurin with siRNA and thru adenoviral overexpression of particular binding domains; and (4) to investigate the role of obscurin's binding to small ankyrin 1 in the assembly, organization and function of the SR.
Mutations in proteins of the contractile apparatus, including some that affect the assembly or stability of contractile elements, have been implicated in hypertrophic cardiomyopathies and muscular dystrophies. The results of our experiments should reveal some of the key mechanisms involved in assembling contractile proteins into sarcomeres and in determining their association with the SR.
描述(由申请人提供):近年来,我们已经了解了大量关于横纹肌中粗丝和细丝的组装,以及关于调节收缩周期所必需的Ca 2+释放和再摄取的蛋白质。然而,我们对将粗丝和细丝整合成肌原纤维的机制,以及组织肌浆网(SR)和横(t-)小管如此规则地围绕肌节的蛋白质知之甚少。最近发现的obscurin为解决这些问题提供了新的方法。
暗蛋白是一种约800 kDa的蛋白质,与肌联蛋白具有结构同源性。它是肌联蛋白超家族中唯一一种至少部分集中在肌节周围的蛋白质,主要集中在M线和Z盘周围。暗蛋白主要由串联的IG结构域组成,但也具有信号传导结构域,并且在其末端COOH-末端,具有集中在网络SR中的小的完整膜形式的锚蛋白1的结合位点。鉴于其明显的集中在M线和Z盘周围的肌原纤维外周的能力以及其对SR膜的完整蛋白的高亲和力,obscurin在肌节和SR的组装和组织中起关键作用。我们提出通过4个具体目标来检验这一一般假设:(1)了解obscurin如何与肌节内的关键结构相结合;(2)了解obscurin如何与收缩器官中的元件结合;(3)评估用siRNA和通过特定结合结构域的腺病毒过表达改变obscurin的活性对肌原纤维和相关膜的形态发生的影响;和(4)研究obscurin与小锚蛋白1的结合在SR的组装、组织和功能中的作用。
收缩器官蛋白质的突变,包括一些影响收缩元件组装或稳定性的突变,与肥厚性心肌病和肌营养不良有关。我们的实验结果应该揭示一些关键机制参与组装收缩蛋白成肌节,并在确定他们的协会与SR。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Na,K-ATPase in skeletal muscle: two populations of beta-spectrin control localization in the sarcolemma but not partitioning between the sarcolemma and the transverse tubules.
骨骼肌中的 Na,K-ATP 酶:β-血影蛋白的两个群体控制肌膜中的定位,但不控制肌膜和横管之间的分配。
- DOI:10.1242/jcs.114.4.751
- 发表时间:2001
- 期刊:
- 影响因子:4
- 作者:Williams,MW;Resneck,WG;Kaysser,T;Ursitti,JA;Birkenmeier,CS;Barker,JE;Bloch,RJ
- 通讯作者:Bloch,RJ
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{{ truncateString('ROBERT J BLOCH', 18)}}的其他基金
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
8265638 - 财政年份:2008
- 资助金额:
$ 1.06万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
7646300 - 财政年份:2008
- 资助金额:
$ 1.06万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
8077961 - 财政年份:2008
- 资助金额:
$ 1.06万 - 项目类别:
Organization of Sarcoplasmic Reticulum in Skeletal Muscle
骨骼肌肌浆网的组织
- 批准号:
7507262 - 财政年份:2008
- 资助金额:
$ 1.06万 - 项目类别:
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