Olfactory receptor signaling in skeletal muscle

骨骼肌中的嗅觉受体信号传导

• 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
• 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

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在创伤性损伤后恢复正常的肌肉结构和功能是必要的。异常的再生会导致肌纤维尺寸、数量和结构的改变。具有异常分支细胞结构的肌纤维常见于各种神经肌肉疾病以及各种物种（包括人类）的严重肌肉损伤后。这些异常的肌纤维很脆弱，含有高比例这些肌纤维的肌肉与虚弱和受伤发生率增加之间存在相关性。含有高水平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尚不清楚。从基础和临床的角度来看，调节肌纤维分支的机制对于阐明具有重要意义。我们最近确定了小鼠气味受体 23 (MOR23) 在小鼠骨骼肌再生中的新作用，并确定了第一个在肌纤维分支中具有功能性作用的分子。 嗅觉神经元中的气味受体信号通过腺苷酸环化酶 3 (AC3) 和蛋白激酶 A (PKA) 依赖性信号通路调节多种粘附和趋化分子的表达。骨骼肌中 MOR23 信号传导调节的下游分子在肌纤维分支中发挥作用尚不清楚。该提案将阐明 MOR23 调节小鼠肌纤维分支的分子途径。根据我们的初步数据，我们假设骨骼肌中 MOR23 的激活会刺激 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发生变化，从而导致肌纤维分支。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。所提出的实验是新颖的，因为它们是第一个从机械角度剖析肌纤维分支调节的实验。气味受体信号通路及其下游分子效应器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学靶点。减少分支肌纤维的数量可能有利于改善肌肉生理学以及肌肉疾病的细胞和基因治疗方法的效率。 公共健康相关性：分支形状异常的肌肉细胞常见于各种肌肉疾病以及严重肌肉损伤后。这些异常的肌肉细胞很脆弱，含有高比例此类细胞的肌肉较弱且更容易受伤。这些分支肌细胞是如何产生的尚不清楚。从基础科学和临床的角度来看，调节这些异常肌肉细胞形成的机制非常重要。我们将使用生化和遗传学方法来操纵我们假设在肌肉细胞分支中发挥作用的几种分子的功能并分析结果。所提出的实验是新颖的，因为它们是第一个从机械角度剖析肌肉细胞分支调节的实验。未来，正在研究的途径可能会导致药物治疗，以消除各种肌肉疾病中的这些异常肌肉细胞。