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Skeletal Muscle. Ca Release Control Inside the Sarcoplasmic Reticulum.

骨骼肌。

基本信息

批准号：
8464002
负责人：
Eduardo Rios
金额：
$ 29.39万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8464002
关键词：
Address Adult Affect Age Aging Amphibia Animals Area Binding Binding Proteins Biochemical Biochemistry Biosensor Body Weight Buffers Calcium Calcium Signaling Calcium-Binding Proteins Calsequestrin Cell physiology Cells DNA Defect Disease Employee Strikes Endowment Evaluation Evolution Exercise Exposure to Failure Fatigue Fiber Figs - dietary Frequencies Functional disorder Gene Expression Gene Silencing Gifts Goals Health Histidine Hour Hybrids Image Immune Immune system Infection Knock-out Language Lead Life Lymphocyte Malignant hyperpyrexia due to anesthesia Mammals Measurement Measures Mediating Membrane Metabolism Methods Mitochondria Modification Monitor Motion Movement Mus Muscle Muscle Cells Muscle Fatigue Muscle Proteins Muscular Dystrophies Myopathy Optics Organ Pathway interactions Pattern Performance Permeability Phenotype Play Predisposition Property Proteins Protocols documentation Regulation Relaxation Research Rest Role STIM1 gene Sarcoplasmic Reticulum Secure Signal Transduction Skeletal Muscle Stimulus Strenuous Exercise System Techniques Testing Therapeutic Time Tissues Transfection Universities Wisconsin Work Yang base calreticulin chromophore circumsporozoite protein combat controlled release density design improved indexing inhibitor/antagonist insight interest killings knock-down millisecond mouse junctate protein muscle aging novel novel strategies overexpression physical conditioning prevent protein distribution research study sensor tool transcription factor triadin voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Ca2+ signaling is a universal language used by cells to react and change. In skeletal muscle its patterns of interest cover multiple time scales: milliseconds -Ca2+ movements that determine contraction and relaxation-; seconds to minutes -when sustained activity may lead to myogenic fatigue- and hours to weeks -patterns that cause changes in gene expression and long-term adaptation-. This study is about inside its cellular store; its quantity, and its concentration, [Ca2+]SR, which conditions Ca2+ signals in every time scale. We ask (1) whether and how [Ca2+]SR controls Ca2+ release from the store, and (2) whether and how calsequestrin and triadin, two strategically located SR proteins, contribute to this control. A technical task, which we call "aim 0", is to image and measure [Ca2+]SR. This was accomplished in the current period and will continue in the next, using novel biosensors -molecules made by the cells themselves- and new hybrid monitors, consisting of high performance small synthetic sensors placed into cells manipulated to make special bio-anchors. To answer questions 1 and 2, we will respectively manipulate [Ca2+]SR while we measure it (aim 1) and force cells to change their endowment of calsequestrin and triadin (aim 2). These goals are now feasible in living animals thanks to a DNA transfection method that works with every protein and can be used also to prevent their synthesis. We propose that [Ca2+]SR -which decays when muscles fatigue- is sustained by SOCE, a universal Ca2+ entry pathway, crucial for mobilizing transcription factors that control gene expression. Using SOCE measures developed in the first period, we propose as aim 3 to define the role of newly discovered molecules of SOCE in the control of [Ca2+]SR. These molecules could be bulwarks against fatigue, and provide powerful tools for experimental alterations of [Ca2+]SR in iterative approaches to the main questions. Ca2+ signals deteriorate in disease, fatigue and aging. Fast Ca2+ signals fail in diseases like hypo-PP, MH susceptibility and central core and minicore, as well as in ageing muscle. Mid-range signaling is affected in fatigue and in an MH-like phenotype of mice lacking calsequestrin. Diseases of long term Ca2+ signals, which show striking parallels in muscle and the immune system, include SCID, a familial immune defect that combines loss of SOCE in lymphocytes and a myogenic myopathy. Our work will advance understanding of these deficits by evaluating roles of specific molecules and their interactions. While only fatigue will be specifically addressed in the present project, questions on the relationships among deficits of function, the intricate pathophysiology and the rational design of therapeutic corrections will be addressed better as we understand what controls stored calcium, and what the stored calcium controls.

描述（由申请人提供）：Ca 2+信号传导是细胞用于反应和变化的通用语言。在骨骼肌中，其感兴趣的模式涵盖多个时间尺度：毫秒-决定收缩和放松的Ca 2+运动-;秒到分钟-持续活动可能导致肌源性疲劳-以及数小时到数周-导致基因表达和长期适应变化的模式。本研究是关于它的细胞内储存，它的数量，和它的浓度，[Ca 2 +]SR，它在每个时间尺度上的条件Ca 2+信号。我们问（1）是否和如何[Ca 2 +]SR控制Ca 2+从存储的释放，和（2）是否和如何calsequestrin和triadin，两个战略定位SR蛋白，有助于这种控制。我们称之为“aim 0”的技术任务是成像和测量[Ca 2 +] SR。这一任务在本期完成，并将在下一个时期继续，使用新型生物传感器-由细胞本身制造的分子-和新的混合监测器，包括放置在细胞中的高性能小型合成传感器，以制造特殊的生物锚。为了回答问题1和2，我们将分别在测量[Ca 2 +]SR时对其进行操作（目的1），并迫使细胞改变其钙螯合蛋白和三聚体的禀赋（目的2）。这些目标现在在活体动物中是可行的，这要归功于一种DNA转染方法，这种方法对每种蛋白质都有效，也可以用来阻止它们的合成。我们提出，[Ca 2 +]SR -肌肉疲劳时衰减-是由SOCE，一个通用的Ca 2+进入途径，动员控制基因表达的转录因子至关重要。使用SOCE措施开发的第一个时期，我们提出的目标3定义的作用，新发现的SOCE分子的控制[Ca 2 +] SR。这些分子可以抵御疲劳，并提供强大的工具，实验改变[Ca 2 +]SR的迭代方法的主要问题。Ca 2+信号在疾病、疲劳和衰老中恶化。快速Ca 2+信号在诸如低PP、MH易感性和中央核心和微核心以及老化肌肉的疾病中失效。中等范围信号传导在疲劳和缺乏钙螯合蛋白的小鼠的MH样表型中受到影响。长期Ca 2+信号的疾病，在肌肉和免疫系统中显示出惊人的相似之处，包括SCID，一种家族性免疫缺陷，结合了淋巴细胞中SOCE的丧失和肌源性肌病。我们的工作将通过评估特定分子及其相互作用的作用来促进对这些缺陷的理解。虽然只有疲劳将在本项目中具体解决，功能缺陷，复杂的病理生理学和合理设计的治疗校正之间的关系的问题将得到更好的解决，因为我们了解什么控制储存钙，什么储存钙控制。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of Ca2+ sparks by Ca2+ and Mg2+ in mammalian and amphibian muscle. An RyR isoform-specific role in excitation-contraction coupling?

哺乳动物和两栖动物肌肉中 Ca2 和 Mg2 对 Ca2 火花的调节。

DOI：
10.1085/jgp.200409105
发表时间：
2004
期刊：
The Journal of general physiology
影响因子：
0
作者：
Zhou,Jingsong;Launikonis,BradleyS;Ríos,Eduardo;Brum,Gustavo
通讯作者：
Brum,Gustavo

Indo-1 derivatives for local calcium sensing.

DOI：
10.1021/cb800258g
发表时间：
2009-03-20
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Bannwarth, Michael;Correa, Ivan R., Jr.;Sztretye, Monika;Pouvreau, Sandrine;Fellay, Cindy;Aebischer, Annina;Royer, Leandro;Ríos, Eduardo;Johnsson, Kai
通讯作者：
Johnsson, Kai

Life and death of a cardiac calcium spark.

心脏钙火花的生与死。