Novel Biomarkers and Genetics of Diabetic Retinopathy

项目摘要 糖尿病视网膜病变（DR）是美国视力丧失的五个最重要的原因之一 每年有12，000 - 24，000例DR相关失明病例。临床表型 DR包括无/轻度DR至危及视力的糖尿病性黄斑水肿（DME）和增殖性黄斑水肿（DR）。 糖尿病视网膜病变（PDR）。DR的严重程度在患者之间变化很大， DR表型变异的基础还不完全清楚。一些糖尿病患者 完全不发生DR，或尽管糖尿病持续时间长但非常轻微的DR。不是所有的糖尿病患者 开发DME或PDR。我们的初步工作提出了新的证据，表明大多数PDR 患者没有并发DME，同样，大多数DME患者没有并发DME。 并发PDR。此外，DME和PDR对抗VEGF药物的反应也不同。的 DME中表型和抗VEGF反应的变异性支持遗传成分 在DR易感性方面。我们研究的目的是确定哪些因素导致了 DR的这种表型变异性，并发现一种“分子谱”， 与疾病的严重程度相关，因此可以用于预测疾病的严重程度。在这项研究中，我们 利用假设驱动和无偏的基因组方法， 序列技术（NGS）研究DR表型变异的分子基础。 我们假设，要么是罕见的基因组因素，要么是 易患不同DR的环境和罕见基因组因素 表型，或防止DR的进展。具体目的包括：1） 在三个民族人群中建立和分离DR、DME和PDR纯表型; 2） 确定和表征影响遗传因子和分子途径， DR的进展和通过使用全外显子组测序的DR的不同子集的分离; 3)使用蛋白质生物标志物确定区分DR表型的蛋白质生物标志物的差异 分析.在该提案中使用下一代测序（NGS）将克服许多困难。 与识别遗传修饰相关的障碍。我们组建了一个独特的团队 DR表型分析和基因组研究专家，以研究DR的遗传变异。我们的 研究将解决在理解DR表型变异性方面的关键科学差距， 将定义与疾病严重程度相关并预测疾病严重程度的“分子谱”。我们的研究结果 可以提供一种用于早期预测疾病严重程度，开发新的生物标志物， 以及改进的治疗靶点，可以防止进展到严重的视力威胁 DR患者中的表型。

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.