Dynamic analysis of mammalian signal transduction pathways

Eric Batchelor LP Systems Biology Section

Confidential (distribute only to Laboratory of Pathology Strategic Visioning Committee Members)

Primary Research Area

- Signal transduction in individual cells - focus on p53 and c-Myc - Long-term time-lapse fluorescence microscopy - Predictive computational modeling - Big Translational Goal: identify novel therapeutic approaches for disease treatment -radiation + novel drug dosing regimen
cell #3 cell #1 cell #2 cell #3

-radiation
cell #1 p53 levels cell #2

p53 levels

time (h)

time (h)

DNA repair and a return to the cell cycle

Senescence

Examples from Research Area

- General interest in developing / using single-cell approaches - Population averaged measurements mask true behavior of cells - Example of current project:

Research Implications
Implications / overlap for LP research:
LP area of expertise in signal transduction pathways important for cancer Focus on variability / heterogeneity of responses in individual cells Computational tools network analysis and image analysis Experimental tools long-term time-lapse imaging

Potential clinical applications:

Primary focus on basic research, but establishing collaborations with clinical researchers Potential development of pathway dynamic perturbations for novel therapeutic approaches, in p53 pathway in particular Development of analytical tools that may be useful for diagnostics

Future Directions
5-year research goals:
Identify role of p53 dynamics on the regulation of p53 target genes Elucidate the regulatory logic of the sub-networks of p53 target genes from single cell transcriptional analysis Apply similar approaches to refine our mechanistic understanding of c-Myc regulation

10-year research goals:

Develop novel therapeutic strategies based on dynamic regulation of p53 / c-Myc High-throughput investigation of transcription factor / signaling dynamics

Challenges & obstacles:

Getting tenure Travel as a limitation to making extramural connections

Collaborators
Within LP: Dave Levens and Dave Roberts c-Myc dynamics and regulation in individual cells Mark Raffeld p53 target gene analysis Maria Merino Arunima Ghosh (LP clinical fellow), p53 dynamics in kidney tumors Outside LP, within NIH: Marston Linehan and Piyush Agarwal (UOB) p53 dynamics in bladder and kidney tumors Jayne Stommel (ROB) p53 and RTK signaling in glioblastoma Federico Bernal (MB) p53 stapled-peptide Outside NIH: Klaus Hahn (UNC Chapel Hill) optogenetic tools to manipulate p53 dynamics