Subproject for Ntziachristos

Intellectual Merit: The ability of cells to dynamically change their gene expression patterns may allow cells to acclimate and survive when exposed to stresses at the expense of homeostasis. Conversely, the lack of ability to explore their genomic landscape may shift the balance towards homeostasis at the expense of the cells' fitness. The adaptive potential of multicellular organisms is critically determined by their capacity to create and employ new behaviors in response to stress. This process depends on the encoded information within the cellular population, both at the genetic, epigenetic, and transcriptional levels. Our data suggest that supranucleosomal chromatin structure is critically involved in the regulation of the potential of cells to explore their transcriptional landscape. In turn, we also have evidence suggesting that this chromatin structure can be controlled via pharmacological agents, morphological cues, and low frequency electromagnetic radiation, stimuli that we refer to as chromatin-modulating plasticity-enhancers (CMPE). The proposed research is transformative because it will provide new knowledge and strategies to regulate chromatin structure in order to enhance the adaptive potential of eukaryotic cells and help induce cellular stemness, with the ultimate goal of facilitating tissue regeneration and function. The proposed research will create a paradigm shift for tissue and regenerative engineering strategies by elucidating factors that govern the restriction of the adaptive potential of eukaryotic cells. Upon completion of the proposal, we expect to: 1) develop a new nanoscale imaging technology to image nanoscale chromatin modifications in vivo; 2) bridge nanoscale imaging and molecular assays; and 3) reversibly increase adaptability of otherwise terminally differentiated cells. Broader Impacts: There is a need to develop technologies to control cell fate in situ with high yield and reduced off target effects, preferably without the use of gene transduction. This project will build the foundations for a new technology that may in the longer-term power regenerative medicine by allowing cell reprogramming, enhancing organ regeneration, and converting this information into tools that can be applied to patient care. The tools developed in this project may improve the survival of neurons in low oxygen/blood supply environment (with the future application to the prevention of neuronal loss due to a stroke) and the regeneration of myocardial tissue after ischemia. Furthermore, the project will help recruit undergraduate students from underrepresented groups while leveraging existing outreach programs at Northwestern University. A rich interactive web presence will be developed for community access to the concepts learned.