Analysis of environmentally-sensitive epigenetic machinery during osteogenic differentiation

成骨分化过程中环境敏感的表观遗传机制分析

• 批准号: 10746311
• 负责人: Nicole Renee Sparks
• 金额: $ 4.55万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-11 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746311
• 关键词: Adult; Affect; Air; Air Pollutants; Air Pollution; Area; Back; Bioinformatics; Bone Development; Bone Injury; Calcium; Cardiovascular Diseases; Chemicals; Chronic; Cities; Communities; Congenital Abnormality; County; Data; Defect; Deposition; Development; Embryo; Endocrine Disruptors; Environment; Environmental Health; Environmental Pollutants; Epigenetic Process; Exclusion; Experimental Designs; Exposure to; Future; Gases; Genetic Predisposition to Disease; Health; Human; Image; Incidence; Industrialization; Infant; Injury; Knowledge; Link; Los Angeles; Malignant Neoplasms; Mass Fragmentography; Medial; Mediating; MicroRNAs; Molecular; Molecular Toxicology; Natural Disasters; Natural Increases; Osteoblasts; Osteogenesis; Outcome; Participant; Particulate Matter; Phenotype; Policies; Pollution; Population Density; Positioning Attribute; Quality Control; Reporting; Respiratory Disease; Risk; Risk Factors; Sampling; Scanning; Science; Skeletal Development; Skeletal system; Source; Stains; System; Testing; Time; Tobacco smoke; Toxic Environmental Substances; Toxicant exposure; Toxicology; Transcriptional Regulation; Vulnerable Populations; Work; adverse birth outcomes; air sampling; aqueous; bone; checkup examination; developmental toxicology; exhaust; follow-up; forest; human embryonic stem cell; in utero; in vitro Model; insight; interest; low socioeconomic status; mRNA Expression; marginalized community; miRNA expression profiling; mineralization; novel; osteogenic; parent grant; pollutant; prenatal; prenatal exposure; reproductive; response; skeletal; toxicant

PROJECT ABSTRACT Impacts of health-related issues are considered proportional to areas with dense air pollution. Air pollution composition is based highly on the area of pollution, however, are made up by general pollutants such as gases from exhaust, particulate matter, and compounds released from burning sources. Although environmental contaminants have been linked to health conditions in the past, direct work assessing air pollution exposure to prenatal bone development is inconclusive. Therefore, the purpose of this supplement is to 1) elucidate the impact of air pollutants on osteogenesis; 2) determine relevant miRNAs related to toxicant exposure and how it impacts bone development; 3) discern specific endocrine-disrupting chemicals found within air pollution; and 4) bring back findings to the communities that it may be impacting. This will be accomplished through direct exposure of pollution to osteogenically-differentiating human embryonic stem cells (hESCs), stained time-lapsed image quantification of mineralization phenotype, determining alterations of mRNA expression throughout differentiation, miRNA-sequencing analysis, and GC/MS data to quantify chemicals within samples. The work proposed within this supplement will be the first study of its kind to demonstrate perturbed osteogenesis in response to air pollution exposure. Additionally, this work will address the gap in knowledge of the dysregulation of miRNAs and resulting bone birth defects. In conjunction with an established human in vitro model and miRNA sequencing analysis, this supplement will continue to advance the evolving fields of molecular toxicology, reproductive toxicology, developmental toxicology, and bioinformatics, as was described in the parent grant. By completion of these studies, I expect to determine a causal relationship between prenatal air pollution exposure and skeletal birth defects. The implications of this work can reach beyond the science community, as these findings may aid in the development of prenatal check-up scans and help inform exposure policies in relation to congenital birth defects.

项目摘要 健康相关问题的影响被认为与空气污染严重的地区成正比。空气污染 污染物的组成主要取决于污染的区域，然而，一般污染物如气体 废气、颗粒物和燃烧源释放的化合物。虽然环境 过去，污染物与健康状况有关，直接工作评估空气污染暴露， 产前骨骼发育是不确定的。因此，本附录的目的是1）阐明 空气污染物对骨生成的影响; 2）确定与毒物暴露相关的相关miRNAs，以及它们如何影响骨生成。 影响骨骼发育; 3）辨别空气污染中发现的特定内分泌干扰化学物质;以及4） 将调查结果带回可能受到影响的社区。这将通过直接 污染暴露于成骨分化的人胚胎干细胞（hESC），染色时间推移 矿化表型的图像定量，确定整个过程中mRNA表达的变化 这些数据包括细胞分化、miRNA测序分析和GC/MS数据，以定量样品中的化学物质。工作 在这一补充中提出的将是第一个证明骨生成扰动的研究， 对空气污染的反应。此外，这项工作将解决知识的失调的差距 和由此导致的骨先天缺陷。结合已建立的人类体外模型和miRNA 测序分析，这一补充将继续推进不断发展的分子毒理学领域， 生殖毒理学、发育毒理学和生物信息学，如母基金中所述。通过 完成这些研究后，我希望能确定产前空气污染暴露之间的因果关系， 和骨骼先天缺陷。这项工作的影响可以超越科学界，因为这些 研究结果可能有助于产前检查扫描的发展，并有助于告知与以下方面有关的暴露政策： 先天性出生缺陷