Novel Biomarkers and Genetics of Diabetic Retinopathy

项目摘要 糖尿病视网膜病变(DR)是美国导致视力丧失的五大原因之一 每年有12,000-24,000例DR相关失明的人口。中国人的临床表型 DR包括无/轻度DR至威胁视力的糖尿病黄斑水肿(DME)和增殖性DR 糖尿病视网膜病变(PDR)。DR的严重程度在不同的患者和生物学上差异很大 DR的表型变异性的基础还不完全清楚。一些糖尿病患者 完全不要发展成糖尿病视网膜病变，或者即使糖尿病持续时间很长，也不要发生非常轻微的糖尿病视网膜病变。不是所有的糖尿病患者 开发DME或PDR。我们的初步工作提供了新的证据，表明大多数PDR 患者没有并发DME，类似地，大多数DME患者也没有 并发PDR。此外，DME和PDR对抗血管内皮生长因子药物的反应也不同。这个 DME的表型和抗血管内皮生长因子反应的可变性支持一种遗传成分 在DR易感性方面。我们研究的目标是确定哪些因素对 DR中的这种表型变异，并发现了一种定量的 与疾病严重程度相关，因此可以用来预测疾病的严重程度。在这项研究提案中，我们 利用假设驱动和无偏倚的基因组方法，使用下一代 序列技术(NGS)研究DR表型变异的分子基础。 我们假设要么是稀有基因组因子(S)，要么是 环境和稀有基因组因素(S)与不同DR的易感性 表型，或防止DR进展的具体目标包括：1) 建立并分离三个民族群体的DR、DME和PDR纯表型；2) 确定和表征影响人类免疫缺陷的遗传因素和分子途径。 应用外显子全序列分析DR的进展和DR不同亚型的分离； 3)使用蛋白质确定区分DR表型的蛋白质生物标志物的差异 分析。在该计划中使用下一代测序(NGS)将克服许多 与识别基因修饰物相关的障碍。我们组建了一支独特的团队 DR表型和基因组研究的专家，以研究Dr.Our的遗传变异 研究将解决在理解DR和DR的表型可变性方面的关键科学差距 将定义一个与疾病严重程度相关并预测其严重程度的“分子图谱”。我们的发现 可为疾病严重程度的早期预测、新生物标志物的开发、 以及改进的治疗目标，可能会防止进展为严重的视力威胁 糖尿病视网膜病变患者的表型。

Project Summary Diabetic retinopathy (DR) is one of the five most important causes of visual loss in the US population with 12,000-24,000 cases of DR-related blindness every year. Clinical phenotypes in DR include no/mild DR to sight threatening diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR). The severity of DR varies widely among patients and the biological underpinning for the phenotypic variability in DR is not completely understood. Some diabetics do not develop DR at all, or very mild DR in spite of long durations of diabetes. Not all diabetics develop DME or PDR. Our preliminary work presents novel evidence that the majority of PDR patients do not have concurrent DME, and similarly the majority of DME patients do not have concurrent PDR. Also, there is differential response to anti-VEGF drugs in DME and PDR. The variability in phenotype and anti-VEGF responsiveness in DME supports a genetic component in DR susceptibility. The goal of our research is to determine what factors are responsible for this phenotypic variability in DR, and discover a “molecular profile” that quantitatively correlates with, and can thus be used to predict disease severity. In this research proposal, we utilize both hypothesis-driven and unbiased genomic approaches using next generation sequence technology (NGS) to investigate the molecular basis of phenotypic variability in DR. We hypothesize that either rare genomic factor(s) or the combination of environmental and rare genomic factor(s) that predispose to different DR phenotypes, or protect against the progression of DR. The specific aims include: 1) establish and segregate pure phenotypes of DR, DME and PDR in three ethnic populations; 2) identify and characterize the genetic factors and molecular pathways that influence the progression of DR and segregation of different subsets of DR by using whole exome sequencing; 3) determine differences in protein biomarkers that differentiate DR phenotypes using protein analysis. Use of next-generation sequencing (NGS) in this proposal will overcome many of the barriers associated with identifying genetic modifiers. We have assembled a unique team of experts in DR phenotyping and genomic studies to investigate genetic variants in DR. Our research will address a critical scientific gap in understanding phenotypic variability in DR and will define a “molecular profile” that correlates with and predicts disease severity. Our findings may provide a tool for early prediction of disease severity, development of novel biomarkers, and improved therapeutic targets that may prevent the progression to severe vision threatening phenotypes in DR patients.