CAREER: Mechanotransduction, transcription, and alternative splicing in cell biology

骨骼肌通过收缩发挥功能，收缩装置通过机械传导将力从肌细胞和细胞内的细胞核传递到质膜。肌细胞中的细胞核受到组织力学和由收缩和松弛引起的细胞质力的影响。在细胞核内，基因被转录成pre- mrna， pre- mrna被加工成mrna，转运到细胞质并翻译成蛋白质。pre - mrna可以通过多种方式加工：选择性剪接允许单个基因通过包含或排除特定区域产生多个转录物。该项目将研究选择性剪接和调节细胞反应的细胞所经历的机械力之间的关系。该项目还将通过为研究生和本科生以及一名博士后提供跨学科、有指导的培训机会，以及在发展中国家服务不足的社区举办科学实验室讲习班（针对6-10岁儿童）和职业讨论小组（针对高中生），推进STEM教育和多样性。骨骼肌的发育是由分子程序和机械力共同驱动的。机械刺激如何控制转录程序和RNA加工机制是肌肉生物学中的一个基本问题。该项目解决了一个总体假设，即机械力激活特定途径，打开/关闭某些转录因子和RNA结合蛋白（rbp），最终控制肌肉细胞中机械敏感基因和剪接异构体的表达。该研究将首先以公正的方式定义响应机械拉伸的信号通路（Aim 1），然后采用候选方法阐明机械敏感转录因子如何调节基因表达程序（Aim 2），最后研究由富含精氨酸（SR）蛋白和CLK1激酶控制的电路如何感知肌肉细胞中的机械力（Aim 3）。这些结果有望促进对肌肉对物理力反应的分子机制的理解，对人类和非人类健康有影响。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Skeletal muscle functions through contraction and the contractile apparatus transduces force both across muscle cells and within cells from the nucleus to the plasma membrane via mechanotransduction. Nuclei in muscle cells are exposed to tissue mechanics and to cytoplasmic forces promoted by contraction and relaxation. Within nuclei, genes are transcribed into pre-mRNAs that are processed into mRNAs, which are transported to the cytoplasm and translated into proteins. Pre-mRNAs can be processed in alternative ways: alternative splicing allows single genes to produce more than one transcript by inclusion or exclusion of specific regions. This project will study the relationships between alternative splicing and mechanical forces experienced by cells that modulate cellular response. The project will also advance STEM education and diversity by providing cross-disciplinary, mentored training opportunities for graduate and undergraduate students, and a postdoctoral associate, and by offering science laboratory workshops (for children aged 6-10) and career discussion panels (for high school students) in underserved communities of a developing country.Skeletal muscle development is driven by both molecular programs and mechanical forces. How mechanical stimuli control transcriptional programs and RNA processing mechanisms is a fundamental question in muscle biology. This project addresses the overarching hypothesis that mechanical forces activate specific pathways that turn on/off certain transcription factors and RNA binding proteins (RBPs) that ultimately control the expression of mechanosensitive genes and splice isoforms in muscle cells. The research will first define in an unbiased manner the signaling pathways that respond to mechanical stretching (Aim 1), then take a candidate approach to elucidate how a mechanosensitive transcription factor regulates gene expression programs (Aim 2), and finally examine how the circuit controlled by arginine-rich (SR) proteins and the CLK1 kinase senses mechanical forces in muscle cells (Aim 3). The outcomes are expected to advance understanding of molecular mechanisms underlying muscle response to physical forces, with implications for human and non-human health.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.