Regulation of nucleocytoplasmic compartmentalization

The National Institute of General Medical Sciences awarded Sanford Research $456,500 on March 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to study the regulation of nucleocytoplasmic compartmentalization and nuclear envelope function.

The research focuses on the nuclear envelope's role in supporting critical cellular functions including genome protection and organization, segregation of transcription and translation, and cell signaling. The project will develop and apply new tools to assess short- and long-term consequences of nuclear envelope ruptures, explore when and where ruptures occur during development, normal tissue use, and injury, and further investigate the mechanisms underlying nuclear envelope-associated progeria. Work builds on prior studies of BioID proximity labeling to characterize protein-protein associations and new nuclear envelope constituents, the discovery of variable rates of regulated nucleocytoplasmic transport across nuclear pore complexes, and the connection between altered cellular energy levels and impacts on RNA export and protein translation.

The period of performance runs from March 1, 2026, through January 31, 2031. Work is performed in Sioux Falls, South Dakota. Sanford Research, a nonprofit biomedical research organization headquartered in Fargo, North Dakota, operates as the prime recipient.

Abstract

The nuclear envelope is a specialized extension of the endoplasmic reticulum that surrounds the eukaryotic cell nucleus, effectively compartmentalizing IT from the rest of the cell. This compartmentalization by the nuclear envelope supports and enables critical functions including protection and organization of the genome, segregation of major cellular processes including transcription and translation, and facilitating numerous cell- signaling events. Defects in many of the constituents of the nuclear envelope lead to a myriad of rare diseases impacting numerous tissues and cell types. Dysfunction of the nuclear envelope is also associated with more common diseases including cancer and neurodegeneration. We have previously studied the structure and function of the nuclear envelope by developing, characterizing and applying bioid proximity labeling to study protein-protein association in living cells, identifying and characterizing new constituents of the nuclear envelope and helping reveal the repair process for nuclear envelope ruptures, and how progeria-associated mutations in constituents of this repair process alter their function. We also discovered that cells have variable rates of regulated nucleocytoplasmic transport across the nuclear pore complexes that span the nuclear envelope. These variable rates, at least in part, are due to altered levels of cellular energy that result from normal processes such as cell spreading and migration and can impact critical cellular processes such as RNA export and protein translation. We will build upon our prior studies of nuclear envelope rupture by developing and applying new tools to assess the short- and long-term consequences of these ruptures and to explore when and where they occur during development, normal tissue use and injury. We will further our studies on the mechanisms underlying nuclear envelope-associated progeria. We will expand upon our studies on the variable rates of nucleocytoplasmic transport to reveal additional consequences to cellular processes. We have developed and validated a new tool that will enable US to close the GAP on our understanding of the nuclear envelope protein constituency in diverse tissues and cell types in vivo, which is likely to reveal new functions of the nuclear envelope and help US understand the diverse cellular mechanisms of disease underlying the myriad of nuclear envelope-associated diseases. Collectively, these studies will address key gaps in our knowledge of how and why the nuclear envelope functionally compartmentalizes the nucleus from the cytoplasm.