Funded Projects

Environmental mechanical cues play an important role in tissue development and regeneration, and these cues are distorted in aged stem cell populations. How aged stem cells transduce mechanical cues to modulate gene expression is the focus of this proposal. Our collaborative quatro consists of groups interested in how stem cell differentiation capacity and self-renewal potential are affected from a mechanical perspective as forces are converted to transcriptional activity. The Suchyna/Sachs group has expertise in biomechanical measurements, and have developed optical force sensors and genetically modified myoblast cell lines to dynamically monitor nuclear stress. The Andreadis group has expertise in tissue engineering, stem cell differentiation and reprogramming. Dr. Gunawan (new CBE faculty) lab has expertise in systems biology, bioinformatics and machine learning methods to interrogate and analyze large data sets. We have shown (Andreadis lab) that senescent myoblasts lose their ability to form functional myotubes, and that this regenerative capacity was restored completely by the transcription factor NANOG. In Aim 1 we propose to study how nuclear mechanical changes occurring in sarcopenia affect myogenesis and satellite cell population self-renewal. In Aim 2 we will determine how stress on the nuclear lamina of aged cells (in response to mechanical stimuli or substrate stiffness) is affected by NANOG. In Aim 3, we will combine high-throughput single-cell transcriptional profiling technology and the state-of-the-art bioinformatics analysis to determine transcriptionally-distinct cell (sub-)populations and to ascertain their gene expression and metabolic signatures. We will apply CALISTA (Clustering and Lineage Inference in Single-Cell Transcriptional Analysis), an in-house bioinformatics toolbox for single-cell transcriptomics analysis developed by the Gunawan group.