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

项目总结 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 影响，占所有儿童失明的高达40%。ROP在以下情况下表现为延迟发病 早产，为预防提供了一个临床窗口。然而，我们缺乏对早期ROP疾病的洞察 因此无法预测哪些婴儿的疾病风险最高，也无法预防ROP。 母体先兆子痫是ROP保护的一种自然模式；对其机制有更深入的了解 在这种情况下，潜在的ROP保护可以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，被认为有多因素的病因，但没有完全建模。 在动物中，分析人类先兆子痫介导的ROP保护最具翻译影响力。 这项科学工作的目的是使用系统生物学分析来理解 母体、胎儿和胎盘病理生物学对早产儿ROP风险的影响及其机制 先兆子痫。这包括特定Aim1的疾病生物标记物分析，基因组和 表观基因组胎盘疾病的特异靶向机制2及胎盘保护的组织学分析 具体目标的机制3.综合职业发展计划的总目标是 候选人通过以下方面的专业知识成为识别新的早期ROP疾病机制的专家 人类人口中的母体、胎儿和胎盘病理生物学，这代表着 应聘者的方法和知识库。培养目标与科学目标相辅相成 并专注于关键的培训差距。这些课程包括：1)高等生物学和 流行病学统计学方法2)综合母体-胎盘病理生物学3)基因组和 表观基因组学方法、数据分析和应用以及4)翻译研究团队的领导。这份职业 开发和研究培训将由一个优秀的、互补的和多学科的 由研究人员和导师组成的指导团队，将在一家拥有良好记录的机构进行 提供优秀的支持，丰富的培训和教育资源。候选人所在的部门致力于 为这位早期临床医生兼科学家的成功，提供任何必要的额外资源来完成 拟议的职业发展和研究目标，并确保持续的受保护的研究时间。这个 建议的方法是一个得到良好支持的培训机制和未来的研究计划，具有重要的意义 翻译承诺继续为改进风险分层、ROP预防和促进 正常的视网膜血管形成。这项全面的培训将为实现 候选人的职业目标是一项独立的、由NIH资助的研究计划，重点是确定 母体、胎儿和胎盘病理生物学对ROP的保护性干预。

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.