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Dynamic analysis

of mammalian signal transduction

pathways

Eric Batchelor

LP Systems Biology Section

Confidential

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

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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 noveltherapeutic approaches for disease

treatment

DNA repair anda return to the cell cycle Senescence

p53le

vels

time (h)

cell #1 cell #2 cell #3

-radiation

p53l

evels

time (h)

-radiation + novel drug dosing regimen

cell #1 cell #2 cell #3

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Examples from Research Area

- General interest in developing / using single-cell approaches

- Population averaged measurements mask true behavior of cells

- Example of current project:

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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

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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

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CollaboratorsWithin 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 tumorsOutside 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