Olfactory receptor signaling in skeletal muscle

骨骼肌中的嗅觉受体信号传导

基本信息

批准号：
8318967
负责人：
Grace K Pavlath
金额：
$ 34.91万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-17 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318967
关键词：
Address Adenylate Cyclase Adhesions Architecture Basic Science Biochemical Genetics Cell Adhesion Cell Therapy Chemotactic Factors Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Future Genetic Human Incidence Injury Knockout Mice Lead Methods Molecular Mus Muscle Muscle Cells Muscle function Myopathy Natural regeneration Neuromuscular Diseases Neurons Odorant Receptors Outcome Pathway interactions Pharmacotherapy Physiological Physiology Play Process Publishing RNA Receptor Signaling Regulation Role Severities Shapes Signal Pathway Signal Transduction Skeletal Muscle Sorting - Cell Movement Specificity Testing Transgenic Mice base cell motility cell type directional cell gene therapy improved in vivo injured mouse model muscle regeneration novel olfactory receptor research study satellite cell

Address Adenylate Cyclase Adhesions Architecture Basic Science Biochemical Genetics Cell Adhesion Cell Therapy Chemotactic Factors Clinical Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Future Genetic Human Incidence Injury Knockout Mice Lead Methods Molecular Mus Muscle Muscle Cells Muscle function Myopathy Natural regeneration Neuromuscular Diseases Neurons Odorant Receptors Outcome Pathway interactions Pharmacotherapy Physiological Physiology Play Process Publishing RNA Receptor Signaling Regulation Role Severities Shapes Signal Pathway Signal Transduction Skeletal Muscle Sorting - Cell Movement Specificity Testing Transgenic Mice base cell motility cell type directional cell gene therapy improved in vivo injured mouse model muscle regeneration novel olfactory receptor research study satellite cell

展开

项目摘要

DESCRIPTION (provided by applicant): Proper muscle regeneration is necessary to restore normal muscle architecture and function after traumatic injury. Aberrant regeneration can result in alterations in myofiber size, number and architecture. Myofibers with an abnormal branching cytoarchitecture are commonly found in various neuromuscular diseases as well as after severe muscle injury in various species, including human. These aberrant myofibers are fragile and a correlation exists between muscles containing a high percentage of these myofibers and weakness and increased incidence of injury. Muscles containing high levels of branched myofibers are unlikely to function in a normal physiologic manner. To date the mechanisms and molecules regulating myofiber branching have been obscure. The mechanisms regulating myofiber branching are significant to elucidate from both a basic and a clinical standpoint. We recently established a novel role for mouse odorant receptor 23 (MOR23) in skeletal muscle regeneration in mice and identified the first molecule with a functional role in myofiber branching. Odorant receptor signaling in olfactory neurons regulates expression of several adhesion and chemoattractant molecules through an adenylyl cyclase 3 (AC3) and protein kinase A (PKA) dependent signaling pathway. The downstream molecules regulated by MOR23 signaling in skeletal muscle that play a role in myofiber branching are unknown. This proposal will elucidate the molecular pathway by which MOR23 regulates myofiber branching in mice. Based on our preliminary data we hypothesize that activation of MOR23 in skeletal muscle stimulates AC3 and protein kinase A (PKA) signaling leading to changes in downstream molecules that regulate muscle cell migration and adhesion and thus, myofiber branching. We will use various genetic mouse models to test the roles of these different molecules in regulating muscle cell migration and adhesion as well as myofiber branching. The proposed experiments are novel because they are the first to mechanistically dissect regulation of myofiber branching. Odorant receptor signaling pathways and their downstream molecular effectors may serve as effective pharmacologic targets for decreasing myofiber branching in various neuromuscular disorders. Decreasing the number of branched myofibers will likely be beneficial for improving both muscle physiology and the efficiency of cell and gene therapy approaches for muscular disorders. PUBLIC HEALTH RELEVANCE: Muscle cells with an abnormal branching shape are commonly found in various muscle diseases as well as after severe muscle injury. These abnormal muscle cells are fragile and muscles containing a high percentage of these types of cells are weaker and become injured more easily. How these branched muscle cells arise is unknown. The mechanisms regulating the formation of these abnormal muscle cells is important to define from both a basic science and a clinical standpoint. We will use biochemical and genetic methods to manipulate the function of several molecules we hypothesize to play a role in muscle cell branching and analyze the outcome. The proposed experiments are novel because they are the first to mechanistically dissect regulation of muscle cell branching. In the future, the pathway under study may lead to drug therapies for eliminating these abnormal muscle cells in various muscle disorders.

描述（由申请人提供）：适当的肌肉再生对于恢复创伤后正常的肌肉结构和功能是必要的。异常再生会导致肌纤维大小，数字和体系结构的变化。具有异常分支细胞结构的肌纤维通常在各种神经肌肉疾病以及包括人在内的各种物种的严重肌肉损伤之后发现。这些异常的肌纤维很脆弱，并且在包含这些肌纤维中很大比例的肌肉之间存在相关性，而弱点和损伤的发生率增加。含有高水平的分支肌纤维的肌肉不太可能以正常的生理方式发挥作用。迄今为止，调节肌纤维分支的机制和分子已经晦涩难懂。调节肌纤维分支的机制对于从基本和临床的角度阐明的机制非常重要。我们最近在小鼠的骨骼肌再生中确立了小鼠气味受体23（MOR23）的新作用，并鉴定出在肌纤维分支中具有功能作用的第一分子。嗅觉神经元中的气味受体信号传导通过腺苷酸环化酶3（AC3）和蛋白激酶A（PKA）依赖性信号传导途径调节几种粘附和趋化分子的表达。在骨骼肌中受MOR23信号传导调节的下游分子在肌纤维分支中起作用是未知的。该建议将阐明MOR23调节小鼠肌纤维分支的分子途径。基于我们的初步数据，我们假设MOR23在骨骼肌中的激活刺激AC3和蛋白激酶A（PKA）信号传导导致调节肌肉细胞迁移和粘附的下游分子的变化，从而变化，从而变化。我们将使用各种遗传小鼠模型来测试这些不同分子在调节肌肉细胞迁移和粘附以及肌纤维分支中的作用。提出的实验是新颖的，因为它们是第一个机械地剖析肌纤维分支的调节的人。气味受体信号通路及其下游分子效应子可以作为减少各种神经肌肉疾病中肌纤维分支的有效药理靶标。减少分支肌纤维的数量可能有益于改善肌肉疾病的肌肉生理和细胞和基因治疗方法的效率。公共卫生相关性：各种肌肉疾病以及严重的肌肉损伤后通常发现具有异常分支形状的肌肉细胞。这些异常的肌肉细胞是脆弱的，含有这些类型细胞的高比例的肌肉较弱，更容易受伤。这些分支肌肉细胞的产生方式尚不清楚。调节这些异常肌肉细胞形成的机制对于从基础科学和临床角度定义很重要。我们将使用生化和遗传方法来操纵我们假设在肌肉细胞分支中发挥作用并分析结果的几个分子的功能。提出的实验是新颖的，因为它们是第一个机械地剖析肌肉细胞分支的调节的人。将来，研究的途径可能导致药物疗法，以消除各种肌肉疾病中这些异常肌肉细胞。