# Structure-Function Mapping of the Nuclear Pore Complex

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2021 · $666,194

## Abstract

PROJECT SUMMARY (Abstract)
The Nuclear Pore Complex (NPC) is a large cylindrical assembly embedded in the nuclear envelope, central for
nuclear function at two related levels. First, as a regulator of transport, the NPC controls signalling access to the
DNA and the passage of genetic information from DNA. Second, the NPC is an important regulator of genes by
binding chromatin and its regulators to control expression states, a phenomenon that is poorly understood at the
molecular level. These pivotal roles in all eukaryotic cells involve dozens of interacting pathways influencing
virtually all aspects of cellular function. As a consequence, disruption of the NPC leads to many human disorders.
Despite this, and though the nuclear transport machinery is a valid and powerful drug target, the NPC and the
nuclear transport machinery have not been a significant part of therapeutic strategies. Arguably, there are two
fundamental reasons why this is the case: (i) we do not know enough about the structure of the NPC to predict
its behavior; (ii) the nuclear transport machinery impacts a bewildering array of cellular functions - thus even with
a deep understanding of its structure, we still require complementary functional information to be able to predict
the outcome of the targeted disruption of key elements of the transport pathway. We propose two Specific Aims
that inform each other in a synergistic fashion. First, we will perform structural mapping of disease-associated
Nup complexes, focusing on components of the cytoplasmic export platform and inner rings that have been
linked to oncogenic and developmental defects. We will use enhanced versions of the methods we have already
successfully deployed to generate high resolution maps of these two regions and their attachment sites. On
completion of this study, we will have mapped most of the NPC at high precision, allowing the two regions to be
seen in the context of the whole NPC assembly. Second, and in parallel, we will map the functions of disease-
associated Nup complexes. We will dissect the functionalities associated with the target Nup complexes, and
determine the defects associated with their alteration - testing the hypothesis that these Nups are linked to
diseases because their disruption alters critical gene expression patterns in a manner distinct from other
nucleoporins. Realizing these aims will generate NPC structure-function maps in unprecedented detail and which
are essential to understanding how different parts of the NPC act together to determine its functionality. This
project will shed light on the nature of numerous disorders associated with human NPC dysfunction; aimed
ultimately to open the nuclear transport machinery to rational and predictive drug design.

## Key facts

- **NIH application ID:** 10149338
- **Project number:** 5R01GM112108-07
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** JOHN D. AITCHISON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $666,194
- **Award type:** 5
- **Project period:** 2015-03-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10149338

## Citation

> US National Institutes of Health, RePORTER application 10149338, Structure-Function Mapping of the Nuclear Pore Complex (5R01GM112108-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10149338. Licensed CC0.

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