# Investigating pulmonary complications due to abnormal collagen/ER stress in Osteogenesis Imperfecta

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $390,000

## Abstract

Project Summary
Osteogenesis imperfecta (OI) is a genetically heterogenous disorder characterized by increased bone fragility
leading to fractures and primarily results from defects in the structure and/or the amount of secreted type I
collagen. While bone fragility is the primary cause of morbidity in OI, pulmonary compromise is the leading cause
of mortality. We and others showed that in OI there is an abnormal bone extracellular matrix (ECM) structure
and type I collagen expressing cells manifest ER stress. Pulmonary mesenchymal derived cells also abundantly
express type I collagen. We hypothesize that OI negatively impacts the lung through two mechanisms; secretion
of an abnormal ECM and chronic ER stress. Using two OI mouse models representing major forms of OI
(missense/loss of function mutations in type I collagen), this proposal will address the hypotheses that mutant
type I collagen secretion and ER stress produces abnormal pulmonary morphology, affects lung cell
differentiation, impairs lung damage recovery, and that altered ECM and ER stress negatively impact signaling
pathways. We address these hypotheses via three aims: 1. Determine the effect of type I collagen mutations on
lung postnatal homeostasis and cell differentiation/communication. Hypothesis: Mutations in type I collagen
genes lead to alterations in OI lung morphology and cell differentiation. Strategy: Using Aga2 and Col1a1+/-
mouse models, the lung will be studied at multiple stages of development via histological/immunohistochemical
(IHC) for differentiation and ECM composition. Using in vitro epithelial cell/fibroblast co-culture organoid
experiments we will define the contribution of abnormal ECM secretion to lung cell differentiation, proliferation,
and apoptosis. 2. Determine the effect of ER stress due to type I collagen mutations on lung cell differentiation,
tissue homeostasis, and reaction to damage. Hypothesis: ER stress in pulmonary type I collagen expressing
cells affect lung cell differentiation and function. Strategy: Using the models from Aim 1, we will determine ER
stress levels in pulmonary cells and whether modulating ER stress in vivo with the chaperone 4-PBA can
influence cell differentiation and homeostasis. Using organoid experiments, we will define the contribution of
chronic ER stress to lung cell differentiation, proliferation, and apoptosis. To study OI lung damage susceptibility,
we will perform in vivo treatment of WT, Aga2, and Col1a1+/- mice with bleomycin to observe the effects of cellular
damage on OI lung tissue in conjunction with the 4-PBA treatment; 3. Identify changes in lung cell population
distribution and gene expression in the context of an abnormal ECM and ER stress. Hypothesis: Lungs with
altered ECM and ER stress affect signaling pathways important in cell differentiation and function. Strategy:
Using the Aga2 and Col1a1+/- mouse models, single-cell RNA-seq cells/tissues derived from lung will be
performed to identify changes in...

## Key facts

- **NIH application ID:** 10556308
- **Project number:** 1R01HL160554-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Jennifer Zieba
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2023-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10556308

## Citation

> US National Institutes of Health, RePORTER application 10556308, Investigating pulmonary complications due to abnormal collagen/ER stress in Osteogenesis Imperfecta (1R01HL160554-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10556308. Licensed CC0.

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