# Mechanisms guiding the fibrillar assembly of SNED1 in the extracellular matrix

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $312,957

## Abstract

Project Summary
The extracellular matrix (ECM) is a complex protein meshwork that constitutes the architectural scaffold of all
tissues. In addition to its structural role, the ECM conveys biochemical signals to cells interpreted by receptors,
like integrins, and controlling diverse cellular functions including adhesion and migration. The ECM is thus a key
regulator of developmental processes and tissue homeostasis. Consequently, alterations in the composition and
assembly of the ECM meshwork have been linked to a plethora of diseases including fibrosis, and cancer.
Important progress toward understanding how the ECM meshwork is built and how the ECM govern cellular
phenotypes have been made by studying major ECM proteins such as fibronectin and collagens. However, using
sequence analysis, we have predicted that nearly 300 proteins can contribute to the ECM meshwork. Knowledge
regarding the roles of these other ECM proteins remains preliminary. This represents a significant gap in our
understanding of the ECM and in our ability to correct disease-causing ECM defects. We have recently become
interested in one of these understudied ECM proteins, SNED1, after having found that it was associated with
more highly aggressive breast cancers. Of clinical relevance, we found that higher SNED1 expression correlated
with a worse prognosis for breast cancer patients. To gain insights into SNED1’s functions, we generated the
first knockout (KO) mouse model of Sned1 and showed that Sned1 is an essential gene, since its KO resulted
in early neonatal lethality due, in part, to craniofacial malformations. Importantly, we recently identified the first
patients with SNED1 variants and they present with craniofacial malformations. Despite these observations, the
mechanisms by which SNED1 contributes to embryonic development and cancer metastasis are unknown.
Using novel tools we developed (antibodies, mouse models, cell lines, purified proteins), we have shown that
SNED1 forms fibers within the ECM scaffold and contributes to its overall organization. In this proposal, we will
test the hypothesis that SNED1 assembly in the ECM and its role in regulating ECM architecture depend on
SNED1’s interactions with other ECM proteins and integrins. Leveraging our unique toolkit and combining our
unique expertise in ECM protein biochemistry and ECM proteomics with state-of-the-art microscopy, we will
conduct a time-resolved structure/function analysis to map which domains of SNED1 mediate its incorporation
in the ECM (Aim 1); determine the role of ECM proteins/SNED1 interactions in SNED1 ECM assembly (Aim 2);
and identify the SNED1 receptors at the cell surface governing SNED1-dependent ECM organization and
responsible for the adhesive property of SNED1 (Aim 3)?
Our goal is to fill critical gaps in our understanding of the fundamental mechanisms leading to ECM assembly,
with respect to SNED1. This is a necessary step toward deciphering how perturbations of these mechanisms
can...

## Key facts

- **NIH application ID:** 10899600
- **Project number:** 5R01GM148423-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Alexandra Naba
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $312,957
- **Award type:** 5
- **Project period:** 2023-08-04 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899600

## Citation

> US National Institutes of Health, RePORTER application 10899600, Mechanisms guiding the fibrillar assembly of SNED1 in the extracellular matrix (5R01GM148423-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10899600. Licensed CC0.

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