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

点击翻译按钮获取中文摘要

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.