Current Research Projects

Transport and Morphology in Reticulated Organelles

The endoplasmic reticulum as an intracellular transport network

The endoplasmic reticulum (ER) forms a dynamic interconnected network of perinuclear sheets and peripheral tubules spanning across the cell. The ER serves as a synthesis site for membrane and secretory proteins, plays an important role in protein quality control, and is a key player in intracellular calcium dynamics. We are exploring the structure-function relationship linking ER morphology and its role as a molecular distribution and sorting system. Specific questions include how the connectivity of network structures affects the rates at which proteins can find each other (diffusion-limited kinetics) or target sites in the network (eg: exit sites for leaving the ER). Using single-molecule tracking data and dynamic imaging of photoactivated protein spreading in the ER, we extract information on the local dynamic behavior of ER membrane proteins. We have also shown that heterogeneities in ER network structure guide protein motion to different regions of the network, and allow for the formation of hot-spots where particles are more likely to find each other. Furthermore, we investigate the role of ER morphology and calcium-binding protein transport in delivering calcium ions for localized release, and have shown that ER morphogen perturbations reduce the magnitude of calcium signaling events. Current work includes exploration of ER structural dynamics, modeling how membrane tension and new growth give rise to the structural features of the peripheral network. Work on these projects is done in collaboration with several experimental groups: the Avezov Lab, the Westrate Lab, and Dr. Obara at the Lippincott-Schwartz Lab.

Papers and preprints:

Spreading and heterogeneity in dynamic networks

Mitochondrial network structure and transport properties

In many cell types, mitochondria fuse into extensive, dynamically rearranging network structures. These network have been proposed to enable homogenization of mitochondrial contents or to provide for selective exclusion of damaged mitochondria; however the overall function of network formation remains unclear. We are exploring how fusion and fission rates couple with mitochondrial transport and mechanics to determine network structure and distribution. In addition, we model the transport of diffusive particles (eg: ions or proteins) through the network, quantifying the extent to which network dynamics and density govern the rate of material mixing versus maintenance of heterogeneity between mitochondria.

Papers and preprints:

Dynamics and Distribution of Neuronal Organelles

Contact dynamics and signal propagation among motile organelles

Recent work has highlighted a plethora of inter-organelle contacts in mammalian cells and has begun to unravel the many biological functions served by such interactions. In the case of globular organelles such as lysosomes, endosomes, phagosomes, peroxisomes, and neuronal mitochondria, intracellular transport is required for the dynamic formation of such contacts. Our group is exploring how transport systems modulate inter-organelle contact events in several different contexts, with a focus on long cellular projections such as neuronal axons. One thread of interest is understanding the maturation of axonal autophagosomes as they fuse with passing lysosomes during their retrograde journey to the cell body for recycling. Another thread focuses on the distribution and maintenance of mitochondria in neurites. In particular, we expore how even distribution of mitochondria throughout the dendritic arbor is supported by specific morphological scaling laws and how distally stationed mitochondria can be maintained in the face of protein turnover by transient interactions between a stationary and a motile pool. Furthermore, we are investigating the structure of the mitochondrial population when individual units can fuse into intermediate-size clusters, and the role of fusion, fission, and transport dynamics in governing the propagation of signals through the 'social network' of mitochondria. Quantitative analysis of mitochondrial distribution and material exchange in the dendritic arbors of Drosophila sensory neurons is compared against model predictions, with the aid of collaborators in the Barnhart group.

Papers and preprints:

Physics of Intracellular Active Transport

Organization, mechanics, and fluid dynamics for motor-driven transport in eukaryotes

Eukaryotic cells must transport components ranging from small molecules to micron-sized vesicles through a complex and heterogeneous physical environment. To aid in this task they employ active transport -- the directed motion of motors along cytoskeletal highways to carry vesicular cargo. While some cargoes are linked directly to molecular motors, others "hitchhike" by indirect attachment to carrier vesicles. Some maintain a high affinity for microtubules, lying in wait for attachment to a passing motor, while others undergo diffusion, driven by thermal or actively generated fluctuations that aid in dispersion in between active motion events. We are investigating the mechanics and dynamics of these transport processes, using a combination of simulations and analytical theory for multi-modal transport phenomena, working in collaboration with experimental researchers who track organelle motion in live cells. Topics of interest include: the mechanics of attachment by hitchhiking cargo, the efficiency of dispersion by multi-modal transport mechanisms at whole-cell scales, the effect of microtubule dynamics and length distribution, and the behavior of motor-driven cargo on parallel microtubule arrays and at neuronal junctions

Papers and preprints: