Molecular Genetics of Dominant Neovascular Inflammatory Vitreoretinopathy

描述(由申请者提供)：这笔资金用于NEI的研究重点，以确定与视网膜退行性疾病有关的基因，并研究炎症性眼病。眼睛是一个免疫特权部位，对局部免疫机制的分子基础知之甚少。我们描述了一个眼内严重炎症且无全身症状的大家族。根据一些独特的临床特征及其遗传方式，将其命名为常染色体显性遗传性新生血管性炎性玻璃体视网膜病变(ADNIV)。在这种眼睛特有的炎症状态下，基因缺陷会触发眼内细胞因子的释放，从而招募炎症细胞。进展性疾病阶段导致ERG b波丧失、进行性视网膜色素变性、周围视野丧失，最终导致视网膜新生血管、视网膜脱离和青光眼。这笔赠款的具体目的是应用先进的分子遗传学技术来发现ADNIV的致病基因，并应用蛋白质组学技术来识别下游的细胞因子信号。我们将利用各种遗传标记策略来缩小连锁间隔，然后通过DNA测序来测试候选基因的突变。眼液样本将被用来筛选疾病不同阶段的细胞因子，在免疫抑制之后，并与其他炎症性眼病进行比较。ADNIV基因的发现意义重大，因为目前还没有已知的专门导致炎症性眼病的基因。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、增殖性玻璃体视网膜病变等。识别ADNIV的特定基因突变将是理解眼睛免疫学基本机制的重要一步。这将使炎症性眼病患者能够进行更有针对性的治疗。ADNIV基因将代表第一个已知的具有眼睛独有的免疫效应的基因。 公共卫生相关性：ADNIV是一种遗传性眼病，与糖尿病视网膜病变、眼内炎症、视网膜脱离和视网膜脱离等更常见的眼病有许多共同特征。这种疾病的基因和下游信号的发现将有助于理解和治疗这些致盲疾病。

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. PUBLIC HEALTH RELEVANCE: ADNIV is an inherited eye disease that shares a number of features with more common eye diseases such as diabetic retinopathy, intraocular inflammation, and retinal detachment, and retinal detachment. Discovery of the gene and downstream signals in this disease will help to understand and treat these blinding diseases.