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Establishing a New Model of Bone Health in Formerly Premature Individuals

为早产儿建立骨骼健康的新模型

基本信息

批准号：
10647677
负责人：
Randal K. Buddington
金额：
$ 19.51万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647677
关键词：
Acceleration Address Adolescence Affect Age Age-Related Bone Loss Alkaline Phosphatase Applications Grants Biological Assay Biological Models Birth Bone Development Bone Growth Bone Resorption Bone Tissue Calcium Choline Clinical Competence Data Development Diagnosis Disease Dual-Energy X-Ray Absorptiometry Egg Yolk Epigenetic Process Epiphysial cartilage Family suidae Fracture Funding Future Gene Expression Goals Health Histology Histone Acetylation Human Impairment Individual Infant Intervention Length Life Live Birth Mechanics Metabolic Bone Diseases Metabolic Marker Minerals Modeling Modification Molecular Monitor Motivation Nutrient Organ Osteocytes Osteogenesis Osteoporosis Pathogenicity Phenotype Plasma Pre-Clinical Model Preclinical Testing Premature Birth Premature Infant Process Property Raman Spectrum Analysis Research Research Project Grants Review Literature Risk Running Sampling Scanning Electron Microscopy Serum Skeletal Development Skeleton Structure Study models System Testing Third Pregnancy Trimester Time Tissues Weaning Work aged body system bone bone fragility bone health bone loss bone mass bone quality burden of illness candidate identification cortical bone density design early adolescence epigenetic marker experimental study feeding fetal gut microbiome gut microbiota high reward high risk human data human subject implementation intervention improved innovation inorganic phosphate long bone negative affect neurodevelopment novel physiologic model porcine model postnatal pre-clinical premature preterm newborn prevent primary endpoint radiological imaging resilience sex skeletal skeletal tissue spine bone structure successful intervention tomography trait

项目摘要

Abstract This Exploratory/Developmental Research Grant will establish a new preclinical model of bone accrual following preterm birth. The rationale is the presence of metabolic bone disease of prematurity that negatively affects the skeletal health of preterm babies and the accumulating evidence of increased bone fragility in former preterm babies entering later decades of life. While there are data for human subjects showing that preterm birth is associated with skeletal deficiencies, successful intervention strategies that target the skeleton are rare, partly because little is known about the underlying mechanisms. A barrier to the field is the lack of a preclinical model in which bone tissue is directly interrogated and mechanistic studies are performed. We have preliminary data of impaired postnatal bone development in a porcine model of prematurity in which we have also identified heightened acetylation of histone 3 in cortical bone osteocytes. Based on these new findings, we propose a novel scientific model system that has the high-risk, high-benefit merit to substantially advance the field. We will test the hypothesis that premature birth in the pig model is associated with diminished bone properties. Our analyses will focus on postnatal bone development through sexual maturity and the possibility of improving early postnatal bone growth. In Aim 1, we assess bone mass, structure and composition by using dual energy x-ray absorptiometry, microcomputed tomography, Raman spectroscopy and backscatter scanning electron microscopy, bone function through mechanical testing to understand whole bone and material properties and will determine if the model replicates the high levels of circulating alkaline phosphatase and low levels of circulating phosphate that are the clinical signs most commonly monitored to diagnose metabolic bone disease of prematurity. These studies will determine if the deficits we have seen up to postnatal day 19 persist through the attainment of sexual maturity at 6 months. In Aim 2, we examine proximate mechanisms (bone resorption and bone formation) and likely ultimate mechanisms (epigenetic reprograming of gene expression and gut microbiome). In Aim 3, we determine if the resulting phenotype is modifiable through use of a feeding formula based on egg yolk, leveraging an already funded study in which the primary endpoint is neuro development. In future studies, we plan to use the model to examine age-related bone loss, but believe it is logical to first evaluate the usefulness of the model to understand how preterm birth affects postnatal skeletal development through early adolescence. Thus, we propose an innovative preclinical, physiological model to study bone accrual following premature birth, its underlying mechanisms and possible treatment. Identifying deficits in bone growth, modeling, remodeling, structure, density and strength in preterm neonates would greatly facilitate the design, preclinical testing, and eventual implementation of interventions that could improve life-long skeletal health.

摘要