# Defining the role of lipid metabolism in nuclear envelope identity and dynamics

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $362,624

## Abstract

PROJECT ABSTRACT
The nuclear envelope is a distinct domain of the endoplasmic reticulum (ER) that serves to surround and protect
the genome. The unique identity of the nuclear envelope is determined by a subset of integral membrane proteins
that execute its distinct functions. After each open mitosis, the nuclear envelope must regain its identity as it
forms from ER-derived membranes. In the current funding period, we showed that regulation of the phosphatidic
acid phosphatase lipin by the nuclear envelope-enriched protein phosphatase CTDNEP1 restricts ER membrane
biogenesis, maintains the lipid composition of the nuclear envelope and contributes to the sealing, size and
protein identity of nuclear envelope. In this project, we want to understand how the lipid composition of the
nuclear envelope is established to control its formation and functions. Our proposed work uses vertebrate tissue
culture cells to define (1) how CTDNEP1 itself is targeted to the nuclear envelope to establish the lipid content
and promote the formation of the nuclear envelope, (2) how local lipid metabolism orchestrates membrane
remodeling during nuclear formation and (3) how membrane sensing by nuclear envelope-associated proteins
contributes to the formation and function of the nuclear envelope. Aim 1 will characterize the nanoscale
organization of CTDNEP1 at the nuclear rim and determine the mechanism that promotes its selective targeting,
retention and stabilization at nuclear envelope subdomains. This will determine how CTDNEP1 recognizes the
nuclear envelope to drive lipid identity. To understand how lipid metabolism in turn controls nuclear envelope
formation, we will determine the lipid species (eg head group and acyl chain composition) necessary for nuclear
membrane remodeling using lipid biosensors, advanced imaging, lipidomics, and candidate screens of lipid
modifying enzymes. Aim 2 builds on our preliminary data in which we uncovered putative membrane-targeting
amphipathic helices (AHs) in known and previously uncharacterized nuclear envelope-associated proteins. We
will directly follow up on two proteins with membrane binding amphipathic helices to determine the significance
of membrane binding to their functions at the nuclear envelope. We will also complete the screen to determine
the putative amphipathic helices for each protein that bind membranes in vitro and the inner nuclear membrane
in vivo. This will allow us to determine if there is a unique, shared code for inner nuclear membrane binding via
amphipathic helices. The completion of this work will elucidate how a unique lipid composition in established at
the nuclear envelope and how the distinct functions of the nuclear envelope are modulated by lipid metabolism.
Defects in the formation of the nuclear envelope from ER-derived membranes leads to genome damage common
to cancer. Mutations in nuclear envelope proteins cause human dystrophies including muscular dystrophy and
progeria. Thus, an understand...

## Key facts

- **NIH application ID:** 10981232
- **Project number:** 2R01GM131004-06A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Shirin Bahmanyar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $362,624
- **Award type:** 2
- **Project period:** 2019-03-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981232

## Citation

> US National Institutes of Health, RePORTER application 10981232, Defining the role of lipid metabolism in nuclear envelope identity and dynamics (2R01GM131004-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10981232. Licensed CC0.

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