Molecular Genetics of Dominant Neovascular Inflammatory Vitreoretinopathy

描述（由申请人提供）：该补助金解决NEI研究优先事项，以确定涉及视网膜退行性疾病的基因和研究炎症性眼病。眼睛是免疫特权部位，局部免疫机制的分子基础知之甚少。我们的特点是一个大家庭，严重的眼内炎症，没有系统的功能。根据其独特的临床特征和遗传方式，将其命名为常染色体显性遗传性新生血管炎性玻璃体视网膜病变（ADNIV）。在这种眼睛特异性的炎症性疾病中，基因缺陷触发了眼内细胞因子的释放，从而招募炎症细胞。进行性疾病阶段导致ERG b-波损失、进行性色素性视网膜变性、周边视野损失，并最终导致视网膜新生血管形成、视网膜脱离和青光眼。该基金的具体目标是应用先进的分子遗传学技术发现ADNIV的致病基因，并应用蛋白质组学技术鉴定下游细胞因子信号。我们将利用各种遗传标记策略来缩小连锁区间，然后通过DNA测序测试候选基因的突变。眼液样本将用于在疾病的各个阶段、免疫抑制后以及与其他炎性眼病相比筛选细胞因子。ADNIV基因的发现是非常重要的，因为没有已知的基因专门引起炎症性眼病。此外，ADNIV基因及其效应细胞因子可能与更常见的炎症性眼病有关，如糖尿病视网膜病变、增生性玻璃体视网膜病变和相关性。确定ADNIV的特异性基因突变将是理解眼睛免疫学基本机制的重要一步。这将为炎症性眼病患者提供更有针对性的治疗。ADNIV基因将代表第一个已知的对眼睛具有免疫作用的基因。

DESCRIPTION (provided by applicant): This grant addresses NEI research priorities to identify the genes involved in retinal degenerative diseases and study inflammatory eye disease. The eye is an immune privileged site where the molecular basis of local immunological mechanisms is poorly understood. We characterized a large family with severe intraocular inflammation and no systemic features. Based on a number of unique clinical features and its pattern of inheritance, it was named Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV). In this eye-specific, inflammatory condition, a gene defect triggers the release of intraocular cytokines that recruit inflammatory cells. Progressive disease stages lead to loss of the ERG b-wave, progressive pigmentary retinal degeneration, peripheral field loss, and eventually retinal neovascularization, retinal detachment, and glaucoma. The specific aims of this grant are to apply advanced molecular genetic techniques to discover the causative gene for ADNIV and proteomic techniques to identify downstream cytokine signals. We will utilize a variety of genetic marker strategies to narrow the linkage interval and then test candidate genes for mutations by DNA sequencing. Eye fluid samples will be used to screen for cytokines at various stages of disease, following immunosuppression, and in comparison to other inflammatory eye diseases. Discovery of the ADNIV gene is highly significant, since there are no known genes that exclusively cause inflammatory eye disease. Moreover, the ADNIV gene and its effector cytokines may be linked to more common inflammatory eye diseases, such as diabetic retinopathy, proliferative vitreoretinopathy, and Relevance. Identifying the specific gene mutation for ADNIV will represent an important step towards understanding the basic mechanisms of eye immunology. This will allow for more targeted therapy for patients with inflammatory eye disease. The ADNIV gene will represent the first known gene with immunological effects exclusive to the eye.