EFEMP1 and drusen formation in the retina

EFEMP1 和视网膜玻璃疣的形成

• 批准号: 8773966
• 负责人: LIHUA Y MARMORSTEIN
• 金额: $ 35.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773966
• 关键词: Age related macular degeneration; Basement membrane; Bruch' s basal membrane structure; Cells; Complement; Complement Activation; Data; Deposition; Development; Drusen; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Event; Eye; Inflammation; Inherited; Intervention; Knock-in Mouse; Knockout Mice; Lead; Macular degeneration; Mus; Mutation; Pathology; Patients; Process; Proteins; Relative (related person); Reporting; Resistance; Retina; Retinal Dystrophy; Role; S1-5 protein; Site; Staging; Stress; Structure of retinal pigment epithelium; Testing; Time; Transgenic Mice; Wild Type Mouse; base; mutant; overexpression; prevent

DESCRIPTION (provided by applicant): The mutation R345W in fibulin-3 (EFEMP1) causes Malattia Leventinese (ML) and Doyne's honeycomb retinal dystrophy (DHRD), two autosomal dominantly inherited macular degenerative diseases with strong similarities to age-related macular degeneration (AMD). Both ML/DHRD and AMD are characterized by drusen. Many factors have been implicated in drusen formation such as complement activation and inflammation. However, it is not clear what triggers these systemic processes to become pathogenic and exert a localized effect in the eye. We found that, in fibulin-3 knock-in (KI) mice carrying the R345W mutation, basal laminar deposit (BLD) develops first, and membranous debris accumulates subsequently within the BLD and in Bruch's membrane to form basal linear deposit (BLinD) before drusen develop. Activated complement components were detected in Bruch's membrane prior to drusen in these mice. Similar findings have been reported by others in AMD. The quantity and site of membranous debris closely correlate with the degree of degeneration in AMD donor eyes. These data indicate that BLD is the initial pathological event, and membranous debris is a critical determinant in drusen formation. BLD is composed of basement membrane material produced by the retinal pigment epithelium (RPE). Membranous debris consists of microvesicles shed from RPE cells. Normally these microvesicles are promptly broken down after their release. Why then do basement membrane material and microvesicles accumulate ultimately leading to drusen in fibulin-3 KI mice and patients with ML/DHRD or AMD? Fibulin-3 is an enzyme inhibitor localized in basement membrane. The R345W mutation does not impair fibulin-3's activity, but makes the protein resistant to degradation leading to its accumulation. Fibulin-3 is also induced by stress. In the KI mice and patients with ML/DHRD or AMD, a high level of fibulin-3 is present in Bruch's membrane and it accumulates in BLD, BLinD, and drusen. However, in fibulin-3 null mice, no BLD or other macular degeneration- associated pathologies were observed. Based on these data, we hypothesize that a high level of fibulin- 3 due to mutation or stress inhibits the turnover of basement membrane material and microvesicles, resulting in BLD and membranous debris accumulation which activates complement and ultimately leads to drusen formation. We will test this hypothesis by determining whether a high level of fibulin-3 or other mechanisms are responsible for BLD/membranous debris accumulation, whether loss of fibulin-3 prevents BLD/membranous debris formation, and when complement activation occurs relative to drusen development and whether it promotes the progression of BLD/membranous debris to drusen. These studies will lead us to a comprehensive understanding of drusen genesis in ML/DHRD and potentially AMD.

描述（由申请人提供）：Fibulin-3（EFEMP1）中的突变R345W导致Malattia Leventinese（ML）和Doyne的Doyne的Honeycomb视网膜营养不良症（DHRD），两种常染色体，两种常染色体显着遗传了与年龄相似的黄斑变性疾病，与年龄相似，与年龄相似。 ML/DHRD和AMD均以Drusen为特征。许多因素与drusen形成有关，例如补体激活和炎症。但是，尚不清楚是什么触发了这些系统的过程，使其成为致病性并在眼中发挥局部作用。我们发现，在带有R345W突变的Fibulin-3敲入（Ki）小鼠中，基础层流沉积物（BLD）首先发展，膜碎屑随后在BLD和BRUCH的膜中积聚，形成基底线性沉积物（在Drusen发育之前）。在这些小鼠中，在DRUSEN之前，在Bruch的膜上检测到活化的补体成分。其他人在AMD中也报道了类似的发现。膜碎片的数量和部位与AMD供体眼的变性程度紧密相关。这些数据表明BLD是最初的病理事件，而膜碎片是drusen形成的关键决定因素。 BLD由视网膜色素上皮（RPE）产生的基底膜材料组成。膜碎片由从RPE细胞中脱落的微泡组成。通常，这些微囊泡在释放后迅速分解。那么，为什么地下膜材料和微囊泡最终会导致fibulin-3 Ki小鼠和ML/DHRD或AMD的患者的Drusen？ Fibulin-3是位于基底膜的酶抑制剂。 R345W突变不会损害Fibulin-3的活性，而是使蛋白质耐降解导致其积累。斐杜蛋白-3也是由应力诱导的。在Ki小鼠和ML/DHRD或AMD的患者中，Bruch膜中存在高水平的fibulin-3，并且在BLD，Blind和Drusen中积聚。但是，在斐杜蛋白-3无效的小鼠中，未观察到没有大bld或其他黄斑变性的病理。基于这些数据，我们假设由于突变或应力引起的高水平的斐杜蛋白-3抑制了基底膜材料和微泡的转换，从而导致大bld和膜碎屑积累，从而激活补体并最终导致Drusen的形成。我们将通过确定高水平的斐杜蛋白3或其他机制是导致bld/膜状碎屑积累的原因，是否损失fibulin-3是否可以阻止bld/膜碎片形成，以及相对于Drousen的发展发生相对于bld/emmembranous debris de truse druse druse druse druse druse druse druse druse druse druse druse druse druse druse，我们将通过确定高水平的腓骨蛋白3或其他机制来检验这一假设。这些研究将使我们对ML/DHRD和可能AMD中的Drusen Genesis有全面的了解。

项目成果

Focus on molecules: fibulin-3 (EFEMP1).

• DOI: 10.1016/j.exer.2009.09.018
• 发表时间: 2010-03
• 期刊: EXPERIMENTAL EYE RESEARCH
• 影响因子: 3.4
• 作者: Zhang, Youwen;Marmorstein, Lihua Y.
• 通讯作者: Marmorstein, Lihua Y.

Association of EFEMP1 with malattia leventinese and age-related macular degeneration: a mini-review.

• DOI: 10.1080/13816810490498305
• 发表时间: 2004-09-01
• 期刊: Ophthalmic genetics
• 影响因子: 1.2
• 作者: Marmorstein, Lihua

Lack of fibulin-3 alters regenerative tissue responses in the primary olfactory pathway.

fibulin-3 的缺乏会改变初级嗅觉通路中的再生组织反应。

• DOI: 10.1016/j.matbio.2009.06.001
• 发表时间: 2009
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Vukovic,Jana;Marmorstein,LihuaY;McLaughlin,PreciousJ;Sasaki,Takako;Plant,GilesW;Harvey,AlanR;Ruitenberg,MarcJ
• 通讯作者: Ruitenberg,MarcJ