During its 120-day life span, a human red blood cell (RBC) circulates a million times in human body and often squeezes through narrow capillaries, exhibiting an amazing ability of control over its shape and mechanical properties under external mechanical stimuli. This collaborative project aims to develop a complete human RBC model coupling the coarse-grained membrane model and cytoskeleton model and to study the molecular regulatory mechanisms in RBC deformation. The complete RBC model is molecularly based, and thus faithful to the underlying nano-scale architecture of the RBC. Upon validation against existing analytical and experimental studies, the complete RBC model will be employed to identify molecular origins of RBC deformation and disorders under combined metabolic activation and mechanical loading.
The intellectual merit of this project resides in the development of the first ever computational whole-cell platform for human erythrocyte. The coarse-grained modeling will establish a direct link between nanostructural changes and observables such as fluctuation, shape, and disorders. When integrated with existing microscopic models of key components in living cells, such as actin and focal adhesion complex, the computational whole-cell platform established herein will help foster transformative progress for the analysis of RBC responses in particular and cell mechanics in general.
The first-ever computational whole-cell platform built upon a detailed blueprint of all the nanostructural members of an entire RBC cell at nanometer resolution will have a revolutionary impact on computational cell biology. The computational platform facilitates identifying the molecular origins of RBC disorders, presenting another key impact of the proposed project. The educational program will enhance minority involvement and participation in science and engineering, and stimulate the interests of students in Penn State and MIT in the emerging field of multiscale modeling of cell mechanics.
The outcomes of this project are several folds. First of all, a whole red blood cell model, bridging the lipid bilayer and the cytoskeleton, has been developed. On the one hand, this model contains sufficient molecular details of Red blood cells, and hence is molecularly faithful. On the other, this model is computationally efficient, capable of simulating large configurational and topological changes of a whole red blood cell. Second, through systematic simulations with this model, the molecular mechanism regarding why red blood cells become very stiff and sticky upon malaria infection is uncovered. It is found that the increased vertical connections between the lipid bilayer and the cytoskeleton due to malaria infection cause the stiffening. This finding provides a solid foundation on developing an effective targeted therapy and design of antimalarial therapeutics. The computational tool established within this project is useful for the biomedical community to simulate many membrane-mediated biological process and uncover the molecular mechanisms of membrane-related diseases. This project enabled institutional collaborations between Penn State and MIT, and international collaborations (between USA and Australia). The project also made possible for the PI to establish a cell mechanics lab to experimentally study a variety of cellular processes at the molecular level. Further, the award from this project provided opportunities to train 2 undergraduate students and 4 PhD students. One student received his PhD with the support of this project. The project have also resulted in 7 conference presentations and 6 journal publications, with 2 more under preparation.
