Genetic polymorphisms in retinal detachment with proliferative vitreoretinopathy

描述（由申请人提供）：K08候选人建议在遗传学，蛋白质组学和生物信息学领域的优秀导师的指导下进行以下研究项目。视网膜脱离（RD）是美国法律的失明的重要原因，终生风险为1/300。增生性玻璃体视网膜病变（PVR）是一种瘢痕形成的条件，形成在5 - 10%的RD。PVR导致手术RD修复失败和失明。PVR尚无有效的药物治疗。目前尚不清楚为什么有些人在良好的手术干预下仍会发生PVR，而另一些人则不会。PVR发病机制中重要基因的多态性可以解释这种差异。我的长期目标是开发一种有效的治疗方法来抑制或预防PVR。为了进行这项研究，我创建了两个PVR动物模型。使用质谱技术iTRAQ，我的初步蛋白质组学分析的视网膜和玻璃体的动物模型的PVR已确定上调的MIF，以及其他候选人，在PVR。已经鉴定了与疾病相关的MIF多态性，其与患有诸如硬皮病的患者中更严重的纤维化相关。因此，我将检验特定的遗传多态性使某些RD患者易患PVR的假设。我的直接主要目标是评价在RD-PVR动物模型中MIF上调的时间进程，并确定在人PVR中已知与MIF信号传导相关的蛋白质的定性和定量差异。我的长期目标是确定调节MIF对实验动物PVR发展的影响，鉴定导致PVR的蛋白质网络和基因多态性，并鉴定可通过治疗靶向的蛋白质。本研究的三个具体目的是：（1）验证MIF在人类和动物模型PVR中均上调的假设。(2)检验疾病相关的MIF多态性在伴有PVR的RD患者中比不伴有PVR的患者更普遍的假设。(3)检验其他iTRAQ候选物在PVR中上调的假设。科学和临床影响。目前尚无治疗PVR的药物。通过鉴定PVR的关键遗传成分，我们可以通过鉴定成功抑制PVR纤维化的新型抗增殖治疗靶点来消除治疗的关键障碍。我们还可以确定生物标志物来检测PVR风险较高的患者。在RD-PVR的遗传基础上获得的知识也可能导致更好地理解其他致盲性纤维化视网膜疾病，如黄斑变性、ROP和增殖性糖尿病视网膜病变。

DESCRIPTION (provided by applicant): The K08 candidate proposes to conduct the following research project under the guidance of outstanding mentors in the fields of genetics, proteomics, and bioinformatics. Retinal detachment (RD) is a significant cause of legal blindness in the US, with a lifetime risk of 1/300. Proliferative vitreoretinopathy (PVR) is a scarring condition that forms in 5-10% of RD. PVR results in failure of surgical RD repair and blindness. There is no effective pharmacologic therapy for PVR. It is not known why some individuals develop PVR despite good surgical intervention and why others do not. Polymorphisms in genes important to the pathogenesis of PVR may explain this difference. My long-term goal is to develop an effective treatment to inhibit or prevent PVR. To perform this research I have created two animal models of PVR. Using the mass spectrometry technique iTRAQ, my preliminary proteomic analysis of retina and vitreous in an animal model of PVR has identified up-regulation of MIF, as well as other candidates, in PVR. Disease-relevant polymorphisms of MIF have been identified which are associated with more severe fibrosis in patients with diseases such as scleroderma. Thus, I will test the hypothesis that specific genetic polymorphisms predispose certain RD patients to PVR development. My immediate primary goals are to evaluate the timecourse of MIF up- regulation in the RD-PVR animal model and to determine the qualitative and quantitative differences in proteins, with known association with MIF signaling, in human PVR. My long-term goals are to determine the impact of modulating MIF on the development of experimental animal PVR, to identify protein networks and gene polymorphisms that lead to PVR, and to identify proteins that can be targeted by therapy. The three specific aims are: (1) Test the hypothesis that MIF is up-regulated in both human and animal model PVR. (2) Test the hypothesis that disease-associated polymorphisms of MIF are more prevalent in RD patients with PVR than without PVR. (3) Test the hypothesis that other iTRAQ candidates are up- regulated in PVR. Scientific and Clinical Impact. There is no drug treatment available for PVR. By identifying key genetic components of PVR we may remove a critical barrier to therapy by identifying novel anti-proliferative treatment targets that successflly inhibit PVR fibrosis. We may also identify biomarkers to detect patients at higher risk for PVR. The knowledge gained on the genetic basis of RD-PVR may also lead to a better understanding of other blinding fibrotic retinal diseases such as macular degeneration, ROP, and proliferative diabetic retinopathy.