EFEMP1 and Drusen Formation in the Retina

EFEMP1 和视网膜中的玻璃疣形成

• 批准号: 7659619
• 负责人: LIHUA Y MARMORSTEIN
• 金额: $ 36.69万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659619
• 关键词: Affect; Age related macular degeneration; Binding; Biological Assay; Bruch' s basal membrane structure; Charge; Data; Defect; Deposition; Diffusion; Disease; Drusen; Elastic Fiber; Elastin; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Family; Filtration; Functional disorder; Histopathology; In Vitro; Inherited; Inorganic Sulfates; Knock-out; Lead; Macular degeneration; Matrix Metalloproteinases; Membrane Structure and Function; Mus; Mutate; Mutation; Nutrient; Pathway interactions; Patients; Property; Proteoglycan; Retina; Retinal Defect; Retinal Dystrophy; Role; S1-5 protein; Site; Skin; Sorsby' s fundus dystrophy; Stratum Basale; Structure of retinal pigment epithelium; Symptoms; Tissue Inhibitor of Metalloproteinase-3; Tissues; Unspecified or Sulfate Ion Sulfates; Variant; fibulin; fibulin-4; insight; mutant

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the cause of macular degeneration. A mutation (R345W) in fibulin-3 (EFEMP1) causes Malattia Leventinese (ML, also known as Doyne's honeycomb retinal dystrophy), an inherited macular degenerative disease with strong similarities to age-related macular degeneration (AMD). Fibulin-3 has been found to aberrantly accumulate beneath the retinal pigment epithelium (RPE) in both ML and AMD and strongly interact with TIMP-3 which is mutated in Sorsby's fundus dystrophy (SFD), another inherited macular degenerative disease. ML, SFD, and AMD are characterized by sub-RPE deposits and share close similarities in symptoms and histopathology. Fibulin-3 belongs to the fibulin family of six known extracellular matrix (ECM) proteins. Recently missense variations in other fibulins have been detected in AMD patients. These data strongly implicate fibulins in a general pathogenic pathway leading to macular degeneration. The functions of fubulins and their mode of involvement in disease are poorly understood. Fibulin-3 has highest homology to fibulin-4 and 5. In preliminary studies, we found that mice lacking fibulin-3 exhibit elastic fiber defects in skin and Bruch's membrane. In contrast, mice carrying the R345W mutation have a severely altered elastic fiber layer and basal linear deposit-like accumulation of materials in Bruch's membrane. Mice lacking fibulin-4 do not form elastic fibers. It has been shown that mice lacking fibulin-5 have disrupted elastic fibers. These findings reveal critical functions of fibulins in elastic fiber assembly and the importance of the elastic layer of Bruch's membrane in macular degeneration. The hypothesis of this proposal is that mutated fibulin-3 alters elastic fiber assembly resulting in its accumulation and changes in Bruch's membrane's structure and function. Bruch's membrane provides a semipermeable filtration barrier for bidirectional diffusion of nutrients and metabolites between the outer retina and the choriocapillaris. Guided by this hypothesis, specific aims are proposed to determine the precise role of fibulin-3 in elastic fiber assembly, how the R345W mutation alters or compromises this function, and how these alterations affect Bruch's membrane's function. These studies will provide fundamental new insights into how changes in Bruch's membrane lead to macular degeneration.

描述（由申请人提供）：该提案的长期目标是了解黄斑变性的原因。 Fibulin-3（EFEMP1）中的一个突变（R345W）导致Malattia Leventinese（ML，也称为Doyne's Honeycomb视网膜营养不良），这是一种遗传性的黄斑变性疾病，与年龄相关的黄斑变性（AMD）很强。已经发现斐杜蛋白3在ML和AMD中异常积聚在视网膜色素上皮（RPE）下方，并与TIMP-3强烈相互作用，TIMP-3在Sorsby的眼底肌营养不良（SFD）中突变，另一种遗传性黄斑脱发性疾病。 ML，SFD和AMD的特征是子RPE沉积物，并在症状和组织病理学方面具有紧密相似之处。 Fibulin-3属于六个已知细胞外基质（ECM）蛋白的斐杜蛋白家族。最近在AMD患者中发现了其他纤维蛋白的错义变化。这些数据强烈暗示腓蛋白在导致黄斑变性的一般致病途径中。少素的功能及其参与疾病的方式知之甚少。 Fibulin-3与Fibulin-4和5。在初步研究中，我们发现缺乏斐杜蛋白3的小鼠在皮肤和BRUCH的膜中表现出弹性纤维缺陷。相反，携带R345W突变的小鼠具有弹性纤维层的严重改变，并且在Bruch膜上材料的基础线性沉积物积累。缺乏纤维蛋白4的小鼠不会形成弹性纤维。已经表明，缺乏纤维蛋白5的小鼠破坏了弹性纤维。这些发现揭示了纤维蛋白在弹性纤维组装中的关键功能以及Bruch膜在黄斑变性中的弹性层的重要性。该提议的假设是突变的斐杜蛋白-3改变了弹性纤维组装，从而导致其积累和Bruch膜的结构和功能的变化。 Bruch的膜提供了一个可半渗透的过滤屏障，用于在视网膜和绒毛膜外乳房之间的营养和代谢物的双向扩散。在这一假设的指导下，提出了具体的目的，以确定斐杜蛋白3在弹性纤维组装中的精确作用，R345W突变如何改变或损害此功能，以及这些改变如何影响Bruch膜的功能。这些研究将为Bruch膜的变化如何导致黄斑变性提供基本的新见解。