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Genetic polymorphisms in retinal detachment with proliferative vitreoretinopathy

增殖性玻璃体视网膜病变视网膜脱离的基因多态性

基本信息

批准号：
9119831
负责人：
Colleen Marie Cebulla
金额：
$ 21.71万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119831
关键词：
Alleles Animal Model Animals Binding Bioinformatics Biological Markers Blindness Cicatrix Clinical Co-Immunoprecipitations Collagen Deposition Development Disease Enzyme-Linked Immunosorbent Assay Failure Fibrosis Frequencies General Population Genes Genetic Genetic Polymorphism Genomic DNA Genotype Goals Human Immigration Individual Inflammation Mediators Inflammatory Inflammatory Response Knockout Mice Knowledge Lead Legal Blindness Macular degeneration Mass Spectrum Analysis Mentors Migration Inhibitory Factor Muller&apos s cell Operative Surgical Procedures Pathogenesis Patients Pharmacotherapy Plasma Proteins Positioning Attribute Proliferative Vitreoretinopathy Promoter Regions Proteins Proteomics RNA Reporting Research Research Project Grants Retina Retinal Detachment Retinal Diseases Role Sampling Scleroderma Signal Transduction Structure of retinal pigment epithelium Techniques Testing Up-Regulation Western Blotting base effective therapy high risk knock-down lifetime risk macrophage migration novel phenylpyruvate tautomerase prevent proliferative diabetic retinopathy repaired targeted treatment

项目摘要

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.

描述(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杰出导师的指导下进行以下研究项目。视网膜脱离(RD)是美国法定失明的一个重要原因，终身致盲的风险为1/300。增殖性玻璃体视网膜病变(PVR)是一种瘢痕形成的情况，在5-10%的RD形成。PVR导致手术后RD修复失败和失明。目前尚无有效的药物治疗PVR。尽管进行了良好的手术治疗，但仍有一些人发生了PVR，而另一些人则没有。PVR发病机制中重要基因的多态性可能解释了这种差异。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，我建立了两个PVR动物模型。使用质谱学技术iTRAQ，我对PVR动物模型的视网膜和玻璃体的初步蛋白质组分析发现，MIF以及其他候选基因在PVR中上调。已发现与疾病相关的MIF基因多态性与硬皮病等疾病患者的更严重的纤维化有关。因此，我将检验这一假设，即特定的基因多态使某些RD患者容易发生PVR。我目前的主要目标是评估RD-PVR动物模型中MIF上调的时间过程，并确定人类PVR中已知与MIF信号相关的蛋白质在质和量上的差异。我的长期目标是确定调节MIF对实验性动物PVR发展的影响，识别导致PVR的蛋白质网络和基因多态性，并识别可以作为治疗靶点的蛋白质。三个具体目的是：(1)验证MIF在人和动物模型PVR中上调的假设。(2)检验有PVR的RD患者中MIF的疾病相关基因多态性比无PVR的RD患者更常见的假设。(3)检验其他iTRAQ候选基因在PVR中上调的假设。科学和临床影响。目前尚无治疗PVR的药物。通过识别PVR的关键遗传成分，我们可以通过识别成功抑制PVR纤维化的新的抗增殖治疗靶点来消除治疗的关键障碍。我们还可以识别生物标记物来检测PVR风险较高的患者。从RD-PVR的遗传学基础上获得的知识也可能有助于更好地了解其他致盲的纤维性视网膜疾病，如黄斑变性、ROP和增殖性糖尿病视网膜病变。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A case of vogt-koyanagi-harada syndrome with persistent dyspnea secondary to laryngeal edema.

喉部水肿继发持续性呼吸困难的沃格特-小柳-原田综合征一例。

DOI：
10.1159/000369003
发表时间：
2014
期刊：
Case reports in ophthalmology
影响因子：
0.4
作者：
Mantopoulos,Dimosthenis;deSilva,BradW;Cebulla,ColleenM
通讯作者：
Cebulla,ColleenM

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.

DOI：
10.1002/gcc.22129
发表时间：
2014-02
期刊：
GENES CHROMOSOMES & CANCER
影响因子：
3.7
作者：
Pilarski, Robert;Cebulla, Colleen M.;Massengill, James B.;Rai, Karan;Rich, Thereasa;Strong, Louise;McGillivray, Barbara;Asrat, Mary-Jill;Davidorf, Frederick H.;Abdel-Rahman, Mohamed H.
通讯作者：
Abdel-Rahman, Mohamed H.

Bilateral optic neuropathy following bite from brown recluse spider (Loxosceles reclusa).

被棕色隐士蜘蛛 (Loxosceles reclusa) 咬伤后出现双侧视神经病变。