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 成分很大程度上取决于污染区域，但由气体等一般污染物组成 来自燃烧源释放的废气、颗粒物和化合物。虽然环保 过去，污染物与健康状况有关，直接开展评估空气污染暴露的工作 产前骨骼发育尚无定论。因此，本补充的目的是 1) 阐明 空气污染物对成骨的影响； 2) 确定与毒物暴露相关的相关miRNA及其如何 影响骨骼发育； 3）识别空气污染中发现的特定内分泌干扰化学物质；和 4) 将调查结果带回可能影响的社区。这将通过直接完成 成骨分化人类胚胎干细胞（hESC）污染的暴露，延时染色 矿化表型的图像量化，确定整个过程中 mRNA 表达的变化 分化、miRNA 测序分析和 GC/MS 数据来量化样品中的化学物质。工作 本补充中提出的研究将是同类研究中第一个证明骨生成受到干扰的研究 对空气污染暴露的反应。此外，这项工作将解决调节失调的知识差距 miRNA 和由此产生的骨出生缺陷。结合已建立的人体体外模型和 miRNA 测序分析，该补充品将继续推动分子毒理学领域的不断发展， 生殖毒理学、发育毒理学和生物信息学，如家长资助中所述。经过 完成这些研究后，我希望确定产前空气污染暴露之间的因果关系 和骨骼出生缺陷。这项工作的影响可能超出科学界，因为这些 研究结果可能有助于产前检查扫描的开发，并有助于为相关的暴露政策提供信息 先天性出生缺陷。