Establishing a New Model of Bone Health in Formerly Premature Individuals

摘要 这项探索性/发展性研究资助将建立一个新的骨累积临床前模型 早产之后。理由是早产儿代谢性骨病的存在， 影响早产儿的骨骼健康， 前早产儿进入后几十年的生活。虽然有人类受试者的数据显示， 早产与骨骼缺陷有关，针对骨骼的成功干预策略 是罕见的，部分原因是对潜在的机制知之甚少。该领域的一个障碍是缺乏一个 临床前模型，其中骨组织被直接询问并进行机理研究。我们有 在猪早产模型中，我们获得了出生后骨发育受损的初步数据， 还鉴定了皮质骨骨细胞中组蛋白3的高度乙酰化。基于这些新发现，我们 提出一个新的科学模型系统，具有高风险，高效益的优点，大大推进 领域我们将在猪模型中检验早产与骨质减少相关的假设 特性.我们的分析将集中在出生后骨骼发育通过性成熟和可能性 促进出生后早期骨骼生长的作用。在目标1中，我们通过使用 双能X射线吸收法、微计算机断层扫描、拉曼光谱和反向散射 扫描电子显微镜，骨功能通过力学测试，了解整个骨和 材料的性质，并将确定该模型是否复制高水平的循环碱性磷酸酶 和低水平的循环磷酸盐，这是最常见的监测诊断的临床体征 早产儿的代谢性骨病。这些研究将确定，我们所看到的赤字， 出生后第19天持续到6个月时达到性成熟。在目标2中，我们检查 近端机制（骨吸收和骨形成）和可能的最终机制（表观遗传 基因表达和肠道微生物组的重编程）。在目标3中，我们确定所得到的表型是否是 通过使用基于蛋黄的喂养配方进行修改，利用已经资助的研究， 主要终点是神经发育。在未来的研究中，我们计划使用该模型来检查年龄相关的 骨质流失，但相信这是合乎逻辑的，首先评估模型的有用性，以了解如何早产 影响出生后骨骼发育直至青春期早期。因此，我们提出了一种创新的临床前， 研究早产后骨增长的生理模型，其潜在机制和可能的 治疗识别早产儿骨生长、建模、重塑、结构、密度和强度的缺陷 新生儿将极大地促进干预措施的设计、临床前测试和最终实施 可以改善终生骨骼健康的方法。

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.