Cadmium and Arsenic Effects on Pyrimidine Biosynthesis in Early Airway Development

镉和砷对早期气道发育中嘧啶生物合成的影响

• 批准号: 10568094
• 负责人: Xin Hu
• 金额: $ 39.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-05 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568094
• 关键词: Address; Adult; Adverse effects; Affect; Anabolism; Arsenic; Atlases; Biology; Cadmium; Carbamyl Phosphate; Cell Communication; Cell Differentiation process; Cell Proliferation; Cell membrane; Cell physiology; Cells; Cellular Structures; Child; Chondroitin Sulfate Proteoglycan; Chondroitin Sulfates; Communities; Complex; Cytidine Diphosphate Choline; Cytoplasm; Cytosine; DNA; DNA biosynthesis; Defect; Development; Disease; Embryo; Environmental Exposure; Environmental Impact; Environmental Risk Factor; Enzymes; Epigenetic Process; Epithelium; Equilibrium; Experimental Models; Exposure to; Fetal Alcohol Exposure; Fetal Development; Food; Foundations; Future; Gene Expression; Genetic Transcription; Glycolysis; Growth; Growth Factor; Growth and Development function; Health; Heavy Metals; Heparitin Sulfate; Human; Impairment; Intervention; Lecithin; Life; Ligase; Link; Lipids; Long-Term Effects; Lung; Lung diseases; Malignant neoplasm of lung; Measurable; Measures; Mediating; Mediator; Metabolic; Metabolic Pathway; Mitochondria; Mitochondrial Proteins; Morphogenesis; Mus; Newborn Infant; Nicotine; Normal Cell; Nucleic Acid Precursors; Output; Pathologic; Pathway interactions; Phenotype; Phospholipid Metabolism; Phospholipids; Pilot Projects; Plasma; Play; Population; Post-Translational Protein Processing; Predisposition; Pregnancy; Pregnant Women; Prevention; Prevention strategy; Production; Proliferating; Protein Glycosylation; Proteoglycan; Proteome; Public Health; Pyrimidine; Pyrimidine Nucleosides; Pyrimidines; RNA; RNA chemical synthesis; Research; Respiratory Disease; Respiratory physiology; Risk; Risk Factors; Role; Signal Transduction; Structure; Testing; Thymine; Transcription Alteration; Translational Research; Uracil; Uridine Diphosphate Sugars; Variant; attenuation; cancer risk; cell growth; cell type; disease prognosis; disorder risk; drinking water; environmental agent; environmental stressor; fetal; health care disparity; health management; innovation; lipid metabolism; lung development; lung health; metabolomics; mouse model; nicotine exposure; novel; nucleoside triphosphate; orotate; oxidation; postnatal; prenatal exposure; pulmonary function; pyrimidine metabolism; single-cell RNA sequencing; small molecule; stem; tool; transcriptome; transcriptomics

Abstract Derangements in airway branching morphogenesis caused by prenatal exposures can have lifelong adverse impact on lung function and increase risks for many major respiratory diseases. Adverse effects of prenatal exposures to alcohol and nicotine are well demonstrated, but the impact of environmental exposures on fetal airway development is less understood. Exposures to heavy metals such as cadmium (Cd) and arsenic (As) are linked to compromised lung health in children and adults. Cd and As cross the placental barrier and are detected ubiquitously in pregnant women, newborns, and children. They are a major public health concern at the US population level, punctuated by alarmingly high exposures in specific communities. Because prenatal exposures to Cd and As are widespread and can have long-term effects on respiratory function, disease risks and prognosis, studies addressing the mechanisms of Cd and As impacting airway development are of urgent and fundamental importance. This application focuses on a novel yet central metabolic pathway, pyrimidine synthesis, found to drive defects in airway branching morphogenesis by our prior research. Pyrimidines are precursors for DNA and RNA synthesis, protein modification and lipid production, and play major regulatory roles in cell growth, proliferation, and differentiation. We hypothesize that dysregulation of de novo biosynthesis of pyrimidines is a critical factor contributing to abnormal airway development and growth. Pyrimidine synthesis is directed by multiple regulatory mechanisms, many susceptible to disruption by heavy metals; the tight control of this pathway is essential to balance between compromised lung development and cancer risk. We will capitalize on established experimental models and use a quantitative and systematic approach, leveraging metabolomics and fluxomics for quantification of affected metabolic flux, linking single- cell transcriptional network variations to the metabolic impact, and evaluating pathological phenotypes with quantitative assessment of airway structure and function. Aim 1 will focus on Cd and As effects on DNA and RNA synthesis as direct output of pyrimidine synthesis and establish a quantitative foundation for studying cell proliferation controlled by nucleic acid precursor availabilities. Aim 2 will focus on proteoglycans, an important mediator of growth factor signaling, which require the pyrimidine, uracil and its products, UDP-sugars for biosynthesis. We will take an innovative approach to investigate the interactions of cell-type specific transcriptional activities and metabolic signals in the form of complex and dynamic networks. Aim 3 will focus on synthesis of phosphatidylcholine in early airway development, the most important component of cell membrane bilayers, which require CTP, and its product CDP-choline as the precursors. Finally, Aim 4 will determine early postnatal lung structure and function to provide information for future translational research on early indicators of Cd and As induced airway developmental abnormalities.

摘要 产前暴露引起的气道分支形态发生紊乱可导致终身不良 影响肺功能并增加许多主要呼吸道疾病风险。产前检查的不良影响 暴露于酒精和尼古丁是很好的证明，但环境暴露对胎儿的影响 对气道发育的了解较少。暴露于重金属，如镉（Cd）和砷（As） 与儿童和成人肺部健康受损有关。镉和砷穿过胎盘屏障， 在孕妇、新生儿和儿童中普遍存在。它们是一个主要的公共卫生问题， 美国的人口水平，在特定社区中惊人的高暴露。因为产前 暴露于镉和砷是广泛的，可以对呼吸功能，疾病风险， 和预后，研究镉和砷影响气道发育的机制是迫切的 和根本的重要性。这种应用程序的重点是一个新的，但中央代谢途径，嘧啶 我们先前的研究发现，合成导致气道分支形态发生缺陷。嘧啶是 DNA和RNA合成，蛋白质修饰和脂质产生的前体，并发挥主要的调节作用， 在细胞生长、增殖和分化中的作用。我们假设，新生的调节失调 嘧啶类化合物的生物合成是导致气道发育异常的一个关键因素， 增长嘧啶合成受多种调节机制的指导，许多容易受到干扰， 重金属;严格控制这一途径对于平衡受损的肺发育至关重要 和癌症风险。我们将利用已建立的实验模型，并使用定量和系统的 方法，利用代谢组学和通量组学来量化受影响的代谢通量，将单个 细胞转录网络变化对代谢的影响，并评估病理表型 气道结构和功能的定量评估。目标1将集中在镉和砷对DNA的影响， RNA合成作为嘧啶合成的直接产物，为研究细胞内RNA的合成奠定了定量基础 由核酸前体可用性控制的增殖。目标2将集中在蛋白聚糖，一个重要的 生长因子信号传导的介质，这需要嘧啶，尿嘧啶及其产物，UDP-糖， 生物合成我们将采取创新的方法来研究细胞类型特异性 转录活动和代谢信号以复杂和动态网络的形式。目标3将重点 在早期气道发育过程中对磷脂酰胆碱合成的影响， 膜双层，这需要CTP，其产物CDP-胆碱作为前体。最后，Aim 4将 确定出生后早期的肺结构和功能，为未来的转化研究提供信息， 镉和砷诱导的气道发育异常的早期指标。