Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

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

Award Number: R01HL160554
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

Group Awards By:

View Award Description

Investigating pulmonary complications due to abnormal collagen/ER stress in Osteogenesis Imperfecta - 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 cell development and gene expression correlated with signaling cascades localized to specific lung cell populations. Completion of these aims will reveal causative mechanisms while introducing novel treatment methods of OI pulmonary dysfunction, the major cause of mortality in OI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $390,000 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	000	4	3/6/2026	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2025 ( Subtotal = $390,000 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	000	3	3/27/2025	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2024 ( Subtotal = $390,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10920 WILSHIRE BLVD STE 500	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	000	2	2/2/2024	NON-COMPETING CONTINUATION	$390,000
														Subtotal = $390,000

Issue Date FY: 2023 ( Subtotal = $390,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	000	1	2/9/2023	NEW	$390,000
														Subtotal = $390,000

Grand Total All Awards = $1,560,000

Top

All Categories

About

Search

Reports

Data Submission

Award Information

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

Award Number: R01HL160554

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer