Regulation of nucleocytoplasmic transport and nuclear pore complex function and assembly.
Our goal is to understand the mechanism for highly selective, bidirectional exchange of proteins and RNA between the nucleus and cytoplasm. Nucleocytoplasmic trafficking is essential for cell function, and precisely regulated during cell division, differentiation and death. At the center of the transport mechanism are the nuclear pore complexes (NPCs), large protein machines embedded in the nuclear envelope. We use yeast, cultured human cells, and zebrafish model systems to address three key questions:
(1) What are the molecular determinants for regulated transport through the NPC? By genetic, molecular and biochemical means, we investigate how NPC proteins interact with transport receptors and facilitate movement.
(2) How are nuclear and cytoplasmic events simultaneously coupled to control mRNA fate? During stress and disease responses, gene expression pathways adapt to target specific transcripts for rapid export, translation and turnover. We are investigating potential roles for NPC-associated factors in coordinating this response.
(3) How do disruptions in NPC function directly impact human disease and aging? We have recently identified specific NPC transport mechanisms that are perturbed in disease and aging processes. These discoveries have opened up entirely new and exciting areas of investigation.
This deeper understanding of the NPC machinery and its regulation provides key mechanistic insights to many human health challenges. Through thorough analysis of NPC transport factors, we have directly linked precise steps in mRNA export to motor neuron diseases such as ALS and LCCS1, and we have uncovered specific nuclear transport pathways that influence aging. We predict that further elucidation of the mechanisms for NPC transport and regulation will uncover other pathogenic mechanisms and identify druggable targets for controlling human disease. Overall, our future work will continue to integrate our discoveries from the analysis of single cell machineries into the context of multicellular organism development and pathophysiology.
Postdoctoral Positions Available
My laboratory has funded positions open for excellent scientists at the postdoctoral level who are interested in pursuing the study of nucleocytoplasmic transport. A current curriculum vitae and three letters of reference should be forwarded for consideration.
The scientific projects in my laboratory currently focus on using either yeast S. cerevisiae or mammalian tissue culture, or Xenopus model systems to understand the mechanism of nuclear transport at the molecular level. Toward this goal, the research directives in my laboratory have focused into three subgroups:
1) analyzing the role of nuclear transport factor interactions with the nuclear pore complex, with particular emphasis on either the role of the FG nucleoporins in the general mechanism or the role of the shuttling mRNA export factor Gle1.
2) studying the mechanism of nuclear pore complex assembly and dynamics, with a focus on developing novel fluorescence, genetic, and structural strategies to dissect the pathway of assembly.
3) Understanding how a novel nuclear inositol polyphosphate signaling pathway regulates mRNA export. We speculate that nuclear inositol signaling plays a key role in coordinating mRNA export and gene transcription responses to extracellular stimuli and intracellular cues.