Identifying and modulating mechanistic cellular paths of quiescence deepening and transition to senescence

About This Grant

Quiescence and senescence are two distinct cellular dormancy states that play critical roles in tissue homeostasis, regeneration, and aging. Despite advances, the molecular mechanisms governing the heterogeneous quiescence depth and its transition to senescence remain unclear. Our long-term goal is to develop strategies to manipulate cellular dormancy states to treat diseases linked to disrupted dormancy- proliferation balance. The objective of this application is to elucidate the transcriptomic and epigenetic paths controlling quiescence depth and its transition into senescence by modulating the Rb-E2F bistable switch threshold. We hypothesize that distinct gene expression and chromatin accessibility changes lead to progressively deeper quiescence by increasing the Rb-E2F switch threshold and delaying E2F target gene induction, and eventually to senescence transition when the switch threshold becomes insurmountable under physiological conditions. We will test our hypothesis by pursuing two specific aims: 1. Identify single-cell transcriptomic and epigenetic paths controlling quiescence depth by modulating the Rb- E2F switch and its effectors by combining innovative single-cell multiomics profiling, computational modeling, and detailed experimental validation. 2. Determine the molecular mechanisms underlying the quiescence-to-senescence transition by measuring and modeling transcriptomic and epigenetic differences between bifurcated quiescent and senescent cells along the transition paths and detailed experimental validation. Our approach is innovative because it integrates cutting-edge single-cell multiomics, advanced computational modeling, and rigorous experimentation to dissect the heterogeneous paths and mechanisms underlying quiescence depth regulation and senescence transition at an unprecedented resolution. The proposed research is significant because it is expected to provide a unified framework linking the Rb-E2F switch threshold to the continuum of cellular dormancy states, advancing our understanding of their molecular basis and interconnections, and informing the development of novel therapeutic strategies to restore tissue homeostasis and function in aging and disease.