Systems level investigation of cell-to-cell communication and cellular heterogeneity in neutrophil apoptosis
Bioinformatics and Theoretical Biology
Immunology
Cell Biology
Final Report Abstract
My research in the Altschuler & Wu labs at the University of California San Francisco (UCSF) aimed to explore the structure and function of cell-to-cell communication networks among immune cells. Cell-to-cell communication networks have critical roles in coordinating diverse organismal processes—however, compared to intracellular signal transduction networks, the function and engineering principles of cell-to-cell communication networks are far less understood. Here, we used a framework that models the input-to-output relationship of intracellular signal transduction networks with a single function—the response-time distribution. We identified a prototypic response-time distribution—the gamma distribution—arising in both experimental data sets and mathematical models of signal-transduction pathways. Applying that distribution to generic models, we found that simple cell-to-cell communication circuits can generate bimodal responsetime distributions and can control synchronization and delay of cell-population responses independently. Finally, we applied our modeling approach to explain otherwise puzzling data on cytokine secretion onset times in T cells. In future research, our approach can be used to predict communication network structure using experimentally accessible input-to-output measurements and without detailed knowledge of intermediate steps. In a second direction of research, I took part in a collaboration project on actin network assembly in neutrophil motility together with the Weiner lab at UCSF. For efficient polarity and migration, cells need to regulate the magnitude and spatial distribution of actin assembly. This process is coordinated by reciprocal interactions between the actin cytoskeleton and mechanical forces. Here we showed that efficient control of actin polymerization-based protrusion requires an additional mechanosensory feedback cascade that indirectly links membrane tension with actin assembly. Mathematical modeling suggested roles for both the direct (mechanical) and indirect (biochemical via PLD2 and mTORC2) feedback loops in organizing cell polarity and motility. This circuit is essential for polarity, motility, and the control of membrane tension.
Publications
- Diverse drugresistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat Commun 7:10690 (2016)
Ramirez M, Rajaram S, Steininger RJ, Osipchuk D, Roth MA, Morinishi LS, Evans L, Ji W, Hsu CH, Thurley K, Wei S, Zhou A, Koduru PR, Posner BA, Wu LF, Altschuler SJ
(See online at https://doi.org/10.1038/ncomms10690) - Membrane tension acts through PLD2 and mTORC2 to limit actin network assembly during neutrophil migration. PLoS Biol 14(6):e1002474 (2016)
Diz-Muñoz A, Thurley K, Chintamen S, Altschuler SJ, Wu LF, Fletcher DA, Weiner OD
(See online at https://doi.org/10.1371/journal.pbio.1002474) - Response-time behaviors of cell-to-cell communication network motifs
Thurley K, Wu LF, Altschuler SJ
(See online at https://doi.org/10.1101/136952)
