EAGER: Exploratory Role of the Cytoskeleton in Anisotropic Regulation of Micrornas in Skeletal Muscles

EAGER：细胞骨架在骨骼肌微RNA各向异性调节中的探索性作用

• 批准号: 1714478
• 负责人: Aladin Boriek
• 金额: $ 17.5万
• 依托单位: Baylor College of Medicine
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1714478&HistoricalAwards=false
• 关键词: EAGER; Exploratory; Role; Cytoskeleton; Anisotropic

Current models of the mechanical function of skeletal muscle are founded upon studies of muscles that are generating or are subjected to forces along the length of the muscle fibers. These measurements of the longitudinal mechanical behavior of muscle have contributed to fundamental knowledge of muscle function at the tissue, cell, and molecular levels of organization. However the diaphragm, the main respiratory muscle, experiences a more complex mechanical environment in which applied forces can be resolved into longitudinal and transverse components. The potential physiological importance of mechanical loads applied to the transverse plane of the muscle in addition to mechanical forces along the length of muscle is suggested by the presence of similar populations of force-transmitting protein complexes at the lateral surface and at the ends of muscle fibers. The research will determine whether the diaphragm can detect and respond separately to longitudinal and transverse loading. This will increase our understanding of diaphragm function with age and disease. Undergraduate students also will receive research experiences form participating in the project.MicroRNAs are a recently discovered class of naturally occurring 22 nucleotides small non-coding RNAs that regulate gene expression either by degradation of target protein-coding mRNAs or by repressing translation in a mechanism similar to small interfering RNA mediated gene silencing. There is little known about the regulation of microRNAs in response to mechanical forces. Furthermore, it is not well understood how the complexity of in vivo mechanical loading in skeletal muscles such as the diaphragm alters the regulation of the microRNAs. It is also unknown whether specific cytoskeletal proteins such as desmin modulate the regulation of mechanosensing microRNAs in the ventilatory pump. The research will determine whether mechanosensing microRNAs such as let-7e-5p and miR-98-5p are regulated by two independent stretch induced signaling pathways that are dependent on the directions of applied mechanical stretch: along muscle fibers and transverse to muscle fibers. Also tested will be whether specific cytoskeletal proteins, e.g. titin and desmin intermediate filaments modulate the mechanosensitive anisotropic regulation of the let-7e-5p and miR-98-5p genes.

当前骨骼肌机械功能的模型是基于对沿肌纤维长度产生或受到力的肌肉的研究而建立的。 这些对肌肉纵向机械行为的测量有助于在组织、细胞和分子水平上了解肌肉功能的基础知识。然而，主要呼吸肌隔膜经历了更复杂的机械环境，其中施加的力可以分解为纵向和横向分量。除了沿着肌肉长度的机械力之外，施加到肌肉横向平面的机械负载的潜在生理重要性通过在肌纤维的侧面和末端存在类似的力传递蛋白质复合物群体来表明。 该研究将确定隔膜是否能够分别检测和响应纵向和横向载荷。 这将增加我们对膈肌功能随年龄和疾病的影响的理解。 本科生还将通过参与该项目获得研究经验。MicroRNA 是最近发现的一类天然存在的 22 个核苷酸的小非编码 RNA，它通过降解目标蛋白编码 mRNA 或通过以类似的机制抑制翻译来调节基因表达小干扰RNA介导的基因沉默。 人们对 microRNA 对机械力的响应调控知之甚少。此外，目前还不清楚骨骼肌（如隔膜）体内机械负荷的复杂性如何改变 microRNA 的调节。目前还不清楚特定的细胞骨架蛋白（例如结蛋白）是否调节通气泵中机械传感 microRNA 的调节。 该研究将确定let-7e-5p和miR-98-5p等机械传感microRNA是否受到两个独立的拉伸诱导信号通路的调节，这两个信号通路依赖于施加机械拉伸的方向：沿着肌纤维和横向于肌纤维。 还测试是否特定的细胞骨架蛋白，例如titin 和 desmin 中间丝调节 let-7e-5p 和 miR-98-5p 基因的机械敏感各向异性调节。

项目成果

Regional diaphragm volume displacement is heterogeneous in dogs

狗的局部隔膜体积位移是异质的

• DOI: 10.1152/ajpregu.00270.2016
• 发表时间: 2017-03
• 期刊: Integrative and Comparative Physiology
• 作者: Greybeck, Brooke;Lu, Raymond;Ramanujam, Arvind;Adeyeye, Mary;Wettergreen, Matthew;Wynd, Shari;Boriek, Aladin M.
• 通讯作者: Boriek, Aladin M.

Anisotropic mechanosensitive pathways in the diaphragm and their implications in muscular dystrophies

膈肌中的各向异性机械敏感通路及其对肌营养不良症的影响

• DOI: 10.1007/s10974-017-9483-7
• 发表时间: 2017-10
• 期刊: Journal of Muscle Research and Cell Motility
• 影响因子: 2.7
• 作者: Pardo, Patricia S.;Lopez, Michael A.;Mohamed, Junaith S.;Boriek, Aladin M.
• 通讯作者: Boriek, Aladin M.

Obesity modulates diaphragm curvature in subjects with and without COPD

肥胖会调节患有或不患有慢性阻塞性肺病的受试者的膈肌曲率

• DOI: 10.1152/ajpregu.00173.2017
• 发表时间: 2017-11
• 期刊: Integrative and Comparative Physiology
• 作者: Boriek, Aladin M.;Lopez, Michael A.;Velasco, Cristina;Bakir, Azam A.;Frolov, Anna;Wynd, Shari;Babb, Tony G.;Hanania, Nicola A.;Hoffman, Eric A.;Sharafkhaneh, Amir
• 通讯作者: Sharafkhaneh, Amir