Grant: Operating Grant - PA: Institute of Genetics (Bridge Funding)

Genome sequencing has begun to reveal the blueprints of life. The daunting challenge now facing the scientific community is to understand how genes are specifically and coordinately expressed to control cell growth and differentiation. The DNA in every eukaryotic cell is encapsulated in the nucleus by an impermeable membrane called the nuclear envelope, while the proteins that regulate its expression are synthesized in the cytoplasm. Cells have made use of this physical separation to control cellular function by regulating the passage of molecules into and out of the nucleus. For example, transit across the nuclear envelope controls the access of activators and repressors of gene expression to the DNA and access of newly synthesized RNA to the protein synthesis machinery in the cytoplasm. Passage between the nucleus and cytoplasm of macromolecules is regulated by elaborate macromolecular gateways termed nuclear pore complexes (NPCs) embedded in the nuclear envelope. In this proposal, we outline experiments to investigate how NPCs control transport during the cell cycle and how this influences chromosome segregation, a process that when disrupted can lead to catastrophic consequences, notably birth defects and cancer. In addition to studying the role of NPCs in nuclear transport, we also propose to investigate the mechanisms that control the assembly of NPCs and their interactions with chromatin, including how NPCs contribute to the epigenetic regulation of gene expression. Defects in these processes have been linked to the pathogenesis of a variety of disorders including Alzheimer's disease, Huntington's disease, type 1 diabetes, heart disease, and the metastatic potential of cancer cells.