Systems-Biology Analysis of Mechanisms Informing Preeclampsia-Mediated ROP Protection

先兆子痫介导的 ROP 保护机制的系统生物学分析

• 批准号: 10225580
• 负责人: Leah A Owen
• 金额: $ 16.56万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225580
• 关键词: Accounting; Address; Animals; Biological; Biological Markers; Birth; Blindness; Blood Vessels; Blood gas; Carrier Proteins; Childhood; Clinical; Complement; Complex; DNA; Data; Data Analyses; Development Plans; Disease; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemiology; Etiology; Event; Foundations; Funding; Future; Genomics; Gestational Age; Goals; High temperature of physical object; Histologic; Histology; Human; Immunohistochemistry; Incidence; Infant; Institution; Intervention; Knowledge; Leadership; Learning; Macronutrients Nutrition; Measures; Mediating; Mediator of activation protein; Mentors; Methodology; Methods; Modeling; Onset of illness; Peptide Hydrolases; Peripheral; Phase; Phenotype; Placenta Diseases; Placental Insufficiency; Population; Pre-Eclampsia; Pregnancy; Premature Birth; Premature Infant; Prevention; Prevention strategy; RNA; Research; Research Personnel; Research Training; Resources; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Risk; Role; Scientist; Serine; Serine Protease; Statistical Methods; Systemic disease; Systems Biology; Testing; Therapeutic; Time; Tissues; Training; Training Support; Translational Research; Umbilical Cord Blood; United States National Institutes of Health; Vascularization; Woman; Work; bisulfite sequencing; career; career development; clinical biomarkers; disorder prevention; disorder risk; early detection biomarkers; education resources; epigenomics; fetal; genome-wide; human data; human disease; improved; insight; knowledge base; multidisciplinary; neovascular; novel; pre-clinical; prevent; programs; prospective; research and development; retina blood vessel structure; risk stratification; specific biomarkers; success

PROJECT SUMMARY Retinopathy of prematurity (ROP) is a neovascular retinal disease of preterm infants that has a significant clinical impact, accounting for up to 40% of all childhood blindness. ROP demonstrates a delayed disease onset after preterm delivery, offering a clinical window for prevention. However, we lack insight into early ROP disease mechanisms and are therefore unable to predict which infants are at greatest disease risk or prevent ROP. Maternal preeclampsia represents a natural model of ROP protection; greater understanding of the mechanisms underlying ROP protection in this setting may allow for identification of novel prediction and prevention strategies. Preeclampsia is a complex disease state thought to have multifactorial etiology, which is incompletely modeled in animals, making analysis of human preeclampsia-mediated ROP protection most translationally impactful. The purpose of this scientific work is to use a systems-biology analysis to understand the contribution of maternal, fetal and placental pathobiology to preterm infant ROP risk and mechanisms in the setting of preeclampsia. This includes disease biomarker analysis in Specific Aim1, an integrated analysis of genomic and epigenomic placental disease mechanisms in Specific Aim 2 and histologic analysis of placental protection mechanisms in Specific Aim 3. The overall goal of the integrated career development plan is to prepare the candidate to become an expert in identifying novel early ROP disease mechanisms through expertise in maternal, fetal and placental pathobiology in human populations, which represents a fundamental transition in both methodology and knowledge base for the candidate. The Training Aims complement Scientific Aims well and focus on critical training gaps. These include didactic and practical learning in 1) Advanced biologic and epidemiology statistical methods 2) Comprehensive maternal-placental pathobiology 3) Genomic and epigenomic methods, data analysis, and application and 4) Translational research team leadership. This career development and research training will be overseen by an outstanding, complementary and multidisciplinary mentoring team of researchers and mentors and will be conducted at an institution with a strong record of providing excellent support, rich training and educational resources. The candidate’s department is committed to the success of this early career clinician-scientist, providing any additional resources necessary to complete the proposed career development and research aims, and ensuring ongoing protected research time. The proposed approach is a well-supported training mechanism and future program of research that holds significant translational promise for continued contribution to improved risk stratification, ROP prevention and promotion of normal retinal vascularization. This comprehensive training will provide a strong foundation toward achieving the candidates career goal of an independent, NIH funded, program of research focused on identification of protective interventions for ROP informed by the contribution of maternal, fetal and placental pathobiology.

项目概要 早产儿视网膜病变（ROP）是一种早产儿视网膜新生血管疾病，具有重要的临床意义。 造成儿童失明的人数高达 40%。 ROP 表现出延迟的疾病发作 早产，提供临床预防窗口。然而，我们缺乏对早期 ROP 疾病的了解 因此无法预测哪些婴儿患病风险最大或预防 ROP。 母亲先兆子痫代表了 ROP 保护的自然模式；更好地了解机制 在这种情况下，潜在的 ROP 保护可能允许识别新的预测和预防策略。 先兆子痫是一种复杂的疾病状态，被认为具有多因素病因，其模型尚未完全建立 在动物中，对人类先兆子痫介导的 ROP 保护的分析最具转化影响力。 这项科学工作的目的是利用系统生物学分析来了解 母体、胎儿和胎盘病理学对早产儿 ROP 风险的影响及其机制 先兆子痫。这包括 Specific Aim1 中的疾病生物标志物分析，即基因组和基因组的综合分析 具体目标2中的表观基因组胎盘疾病机制和胎盘保护的组织学分析 具体目标 3 中的机制。综合职业发展计划的总体目标是为 候选人成为通过专业知识识别新型早期 ROP 疾病机制的专家 人类的母体、胎儿和胎盘病理学，这代表了一个根本性的转变 候选人的方法论和知识基础。培训目标很好地补充了科学目标 并关注关键的培训差距。其中包括以下方面的教学和实践学习：1) 高级生物学和 流行病学统计方法 2) 综合母体胎盘病理学 3) 基因组和 表观基因组方法、数据分析和应用；4) 转化研究团队的领导。这个职业 开发和研究培训将由杰出的、互补的、多学科的人员监督 由研究人员和导师组成的指导团队，并将在具有良好记录的机构进行 提供卓越的支持、丰富的培训和教育资源。候选人所在部门承诺 为了这位早期职业临床医生科学家的成功，提供完成所需的任何额外资源 拟议的职业发展和研究目标，并确保持续受保护的研究时间。这 拟议的方法是一个得到充分支持的培训机制和未来的研究计划，具有重要意义 持续为改进风险分层、ROP 预防和促进 正常的视网膜血管形成。此次综合培训将为实现这一目标奠定坚实的基础。 候选人的职业目标是一个独立的、由美国国立卫生研究院资助的研究项目，重点是识别 根据母体、胎儿和胎盘病理学的贡献，对 ROP 采取保护性干预措施。