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

项目摘要 早产儿视网膜病变（Retinopathy of premature，ROP）是一种发生于早产儿的新生血管性视网膜疾病， 影响，占所有儿童失明的40%。ROP表现出延迟的疾病发作后， 早产，为预防提供了一个临床窗口。然而，我们缺乏对早期ROP疾病的了解， 因此，他们无法预测哪些婴儿处于最大的疾病风险或预防ROP。 母亲先兆子痫代表ROP保护的自然模型;更好地了解机制 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，被认为有多因素病因，这是不完全建模 在动物中，使人先兆子痫介导的ROP保护的分析最具预防影响力。 这项科学工作的目的是使用系统生物学分析来了解 母体、胎儿和胎盘病理生物学对早产儿ROP的风险和机制， 先兆子痫这包括Specific Aim 1中的疾病生物标志物分析，基因组和 表观基因组胎盘疾病机制在特异性目的2和胎盘保护的组织学分析 具体目标3。综合职业发展计划的总体目标是编制 候选人成为通过专业知识识别新的早期ROP疾病机制的专家， 母体，胎儿和胎盘病理生物学在人群中，这代表了一个根本的转变， 候选人的方法和知识基础。培训目标与科学目标相辅相成 并关注关键的培训缺口。这些包括教学和实践学习1）先进的生物和 流行病学统计方法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; 4）转化研究团队领导。这个职业 发展和研究培训将由一个杰出的，互补的和多学科的监督 指导团队的研究人员和导师，并将在一个机构进行了良好的记录， 提供良好的支持，丰富的培训和教育资源。候选人所在部门承诺 为这位早期职业临床医生-科学家的成功，提供任何必要的额外资源， 建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。的 提出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，具有重要意义 翻译承诺继续为改善风险分层、ROP预防和促进 正常视网膜血管化。这种全面的培训将为实现 候选人的职业目标是一个独立的，NIH资助的，研究计划的重点是识别 通过母体、胎儿和胎盘病理生物学的贡献，对ROP进行保护性干预。

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.