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Principal Investigator: Jennifer Zieba
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $390,000
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Address><Affect><Anatomic Abnormality><Anatomical Abnormality><Apoptosis><Apoptosis Pathway><Autoregulation><Basement membrane><Bleo><Bleomycin><Body Tissues><Bone Diseases><Brittle bone disorder><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Function><Cell Interaction><Cell Physiology><Cell Process><Cell Signaling><Cell secretion><Cell-Extracellular Matrix><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Secretion><Cellular injury><Chaperone><Chronic><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Collagen><Collagen Gene><Collagen Type I><Communication><Defect><Deformity><Development><Disease><Disorder><Dysfunction><ECM><ER stress><Environment><Epithelial Cells><Exhibits><Expression Signature><Extracellular Matrix><Fibroblasts><Foundations><Fracture><Fragilitas Ossium><Frequencies><Functional disorder><Future><Gene Expression><Gene Expression Profile><Genes><Genetic Alteration><Genetic Change><Genetic defect><Histologic><Histologically><Homeostasis><Impairment><In Vitro><Infection><Intracellular Communication and Signaling><Knowledge><Lead><Lung><Lung Alveolar Epithelia><Lung Diseases><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung damage><Mesenchymal><Methodology><Methods><Mice><Mice Mammals><Modeling><Molecular><Molecular Chaperones><Morbidity><Morbidity - disease rate><Morphology><Murine><Mus><Mutation><Myofibroblast><Non-Polyadenylated RNA><Organoids><Osteoblasts><Osteogenesis Imperfect><Osteogenesis Imperfecta><Patients><Pb element><Perinatal Mortalities><Perinatal lethality><Perinatal mortality demographics><Phenotype><Physiological Homeostasis><Physiopathology><Population><Population Distributions><Predisposition><Programmed Cell Death><Proliferating><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Incompetence><Pulmonary Insufficiency><Pulmonary Regurgitation><Pulmonary Valve Incompetence><Pulmonary Valve Insufficiency><Pulmonary Valve Regurgitation><RNA><RNA Gene Products><Reaction><Recovery><Reporting><Ribonucleic Acid><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure of parenchyma of lung><Subcellular Process><Susceptibility><Therapeutic><Tissues><Type 1 Collagen><Validation><Work><alveolar epithelium><biological signal transduction><bone><bone disorder><bone fracture><bone fragility><brittle bone disease><cell damage><cell injury><cellular damage><cellular differentiation><damage to cells><defined contribution><developmental><disability><disease of the lung><disorder of the lung><endoplasmic reticulum stress><environmental stresses><environmental stressor><experiment><experimental research><experimental study><experiments><fragile bone><gene expression pattern><gene expression signature><genome mutation><heavy metal Pb><heavy metal lead><improved><in vivo><injury to cells><insight><loss of function mutation><lung development><lung disorder><lung function><lung injury><lung insufficiency><mortality><mouse model><murine model><mutant><novel><pathophysiology><perinatal deaths><post-natal development><postnatal><postnatal development><pulmonary><pulmonary damage><pulmonary function><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><transcriptional profile><transcriptional signature><validations>