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

目前骨骼肌机械功能的模型是建立在对肌肉的研究基础上的，这些肌肉沿着肌纤维的长度产生力或经受力沿着。 肌肉纵向力学行为的这些测量有助于在组织、细胞和分子水平上了解肌肉功能的基本知识。然而，作为主要呼吸肌的横膈膜经历更复杂的机械环境，其中所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，施加到肌肉的横向平面的机械载荷的潜在生理重要性由在侧表面和在肌纤维末端处存在类似的力传递蛋白复合物的群体来建议。 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。 这将增加我们对随着年龄和疾病的隔膜功能的了解。 MicroRNA是近年来发现的一类天然存在的22个核苷酸的小的非编码RNA，其通过降解编码靶蛋白的mRNA或抑制翻译来调节基因表达，其机制类似于小干扰RNA介导的基因沉默。 关于microRNA响应于机械力的调节知之甚少。此外，还没有很好地理解骨骼肌如膈肌中体内机械负荷的复杂性如何改变microRNA的调节。也不知道是否特定的细胞骨架蛋白，如结蛋白调节的调节mechanosensingmicroRNA在排泄泵。 该研究将确定诸如let-7 e-5 p和miR-98- 5 p的机械传感microRNA是否受到两个独立的拉伸诱导信号通路的调节，这两个信号通路取决于施加的机械拉伸的方向：沿着肌纤维和横向于肌纤维。 还将测试特定的细胞骨架蛋白，例如肌联蛋白和结蛋白中间丝是否调节let-7 e-5 p和miR-98- 5 p基因的机械敏感性各向异性调节。

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.