Ma, Lan

Permanent URI for this collectionhttps://hdl.handle.net/10735.1/3058

Lan Ma is an assistant professor in Bioengineering. Her research interests include

  • Elucidate mechanisms underlying circadian rhythms in a model system using an integrated mathematical and experimental approach
  • Mathematical modeling of protein-protein interaction in relationship to programmed cell death
  • Robustness analysis of circadian rhythm and other oscillatory biological systems
  • Applying control theory and dynamical systems theory to the studies of biological systems
She joined the faculty in 2010 and is the head of the Functional Cellular Networks Laboratory.

Learn more about Dr. Ma's research on her home and Research Explorer pages.

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Recent Submissions

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    Mir-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced P53 Oscillations in Breast Cancer Cells
    (Public Library of Science) Moore, Richard; Ooi, Hsu Kiang; Kang, Taek; Bleris, Leonidas; Ma, Lan; 55515673900 (Ma, L); Moore, Richard; Ooi, Hsu Kiang; Kang, Taek; Bleris, Leonidas; Ma, Lan
    The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understanding of the regulatory mechanism and the role of microRNAs-forming feedback loops with the p53 core remains elusive. Here we have identified from literature that there exist three classes of microRNA-mediated feedback loops revolving around p53, all with the nature of positive feedback coincidentally. To explore the relationship between the cellular performance of p53 with the microRNA feedback pathways, we developed a mathematical model of the core p53-MDM2 module coupled with three microRNA-mediated positive feedback loops involving miR-192, miR-34a, and miR-29a. Simulations and bifurcation analysis in relationship to extrinsic noise reproduce the oscillatory behavior of p53 under DNA damage in single cells, and notably show that specific microRNA abrogation can disrupt the wild-type cellular phenotype when the ubiquitous cell-to-cell variability is taken into account. To assess these in silico results we conducted microRNA-perturbation experiments in MCF7 breast cancer cells. Time-lapse microscopy of cell-population behavior in response to DNA double-strand breaks, together with image classification of single-cell phenotypes across a population, confirmed that the cellular p53 oscillations are compromised after miR-192 perturbations, matching well with the model predictions. Our study via modeling in combination with quantitative experiments provides new evidence on the role of microRNA-mediated positive feedback loops in conferring robustness to the system performance of stress-induced response of p53.;
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    Quantifying the Rhythm of KaiB-C Interaction for In Vitro Cyanobacterial Circadian Clock
    Ma, Lan; Ranganathan, R.
    An oscillator consisting of KaiA, KaiB, and KaiC proteins comprises the core of cyanobacterial circadian clock. While one key reaction in this process-KaiC phosphorylation-has been extensively investigated and modeled, other key processes, such as the interactions among Kai proteins, are not understood well. Specifically, different experimental techniques have yielded inconsistent views about Kai A, B, and C interactions. Here, we first propose a mathematical model of cyanobacterial circadian clock that explains the recently observed dynamics of the four phospho-states of KaiC as well as the interactions among the three Kai proteins. Simulations of the model show that the interaction between KaiB and KaiC oscillates with the same period as the phosphorylation of KaiC, but displays a phase delay of ~8 hr relative to the total phosphorylated KaiC. Secondly, this prediction on KaiB-C interaction are evaluated using a novel FRET (Fluorescence Resonance Energy Transfer)-based assay by tagging fluorescent proteins Cerulean and Venus to KaiC and KaiB, respectively, and reconstituting fluorescent protein-labeled in vitro clock. The data show that the KaiB:KaiC interaction indeed oscillates with ~24 hr periodicity and ~8 hr phase delay relative to KaiC phosphorylation, consistent with model prediction. Moreover, it is noteworthy that our model indicates that the interlinked positive and negative feedback loops are the underlying mechanism for oscillation, with the serine phosphorylated-state (the "S-state") of KaiC being a hub for the feedback loops. Because the kinetics of the KaiB-C interaction faithfully follows that of the S-state, the FRET measurement may provide an important real-time probe in quantitative study of the cyanobacterial circadian clock. © 2012 Ma, Ranganathan.

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