Novel Mouse Models of Age-Related Macular Degeneration

年龄相关性黄斑变性的新型小鼠模型

• 批准号: 7235611
• 负责人: Jayakrishna Ambati
• 金额: $ 32.18万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7235611
• 关键词: Adherence; Age; Age related macular degeneration; Age-Months; Amyloid; Amyloid beta-Protein; Angiography; Animal Model; Atrophic; Binding Proteins; Blindness; Bone Marrow; CCL2 gene; Cell secretion; Cells; Choroid; Choroidal Neovascularization; Code; Complement 5a; Complement component C5; Data; Deposition; Development; Disease regression; Drusen; Elderly; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Eye; Frozen Sections; Glass; Histopathology; Human; Immunoglobulin G; Immunohistochemistry; In Situ; In Vitro; Knock-out; Knockout Mice; Lipofuscin; Mus; Numbers; Ophthalmoscopy; Pathology; Patients; Photography; Production; Proteins; Research Personnel; Serum; Slide; Spottings; Stem cells; Structure of retinal pigment epithelium; Testing; Transplantation; Vascular Endothelial Growth Factors; Vitronectin; Western Blotting; Wild Type Mouse; adeno-associated viral vector; age related; aged; chemokine; complement C3 precursor; insight; macrophage; monocyte chemoattractant protein 1 receptor; mouse model; novel; prevent; programs; protein degradation; response; senescence; subretinal injection; therapy development

DESCRIPTION (provided by applicant): Introduction: Age-related macular degeneration (AMD) is the leading cause of elderly blindness in the U.S. Absence of good animal models has limited mechanistic understanding and thwarted development of therapies. We observed that mice genetically deficient either in the macrophage chemokine CCL2 or its cognate receptor CCR2 develop the pathological hallmarks of AMD in an age-dependent fashion. Preliminary Data: (1) CCL2-/- and CCR2-/- mice develop lipofuscin, drusen, geographic atrophy, and choroidal neovascularization (CNV) as they age. (2) Complement C5 and IgG are deposited in the retinal pigmented epithelium (RPE) and choroid of both knockout strains as they age, as in patients with AMD. (3) These findings are not present in age-matched wild-type mice. (4) Macrophages infiltrate into the choroid of aged wild-type mice but not knockouts in large numbers. (5) C5a and IgG upregulate RPE secretion of CCL2. (6) C5a and IgG upregulate RPE and choroidal endothelial cell secretion of vascular endothelial growth factor (VEGF), consistent with CNV development. (7) Macrophages are immobilized by and adhere to C5a & IgG. Hypotheses: (1) The accumulation of drusen and lipofuscin associated with senescence in CCL2-/- or CCR2- /- mice is due to impaired clearance by scavenger macrophages, whose recruitment is impaired in the absence of CCL2 or its receptor CCR2, and ultimately leads to geographic atrophy and CNV. (2) Rescue of CCL2 or CCR2 function can prevent or regress AMD-like pathology in knockout mice. Specific Aims: (1) To quantify the development of AMD-like features in CCL2-/- or CCR2-/- mice by ophthalmoscopy, angiography, and histopathology, compared to age-matched wild-type mice. (2) To demonstrate that protein deposits found in the RPE and choroid of senescent CCL2-/- or CCR2-/- mice stimulate CCL2 and VEGF production, and that macrophages adhere to and degrade these protein deposits. (3) To demonstrate that rescue of CCL2 or CCR2 function inhibits or regresses AMD-like pathology in elderly CCL2-/- or CCR2-/- mice. Significance: These studies will provide mechanistic insights into and more effective treatments for AMD.

简介：老年性黄斑变性(AMD)是美国老年性失明的主要原因。缺乏良好的动物模型限制了对机制的理解，阻碍了治疗方法的发展。我们观察到，无论是巨噬细胞趋化因子CCL2或其同源受体CCR2的遗传缺陷小鼠，都会以年龄依赖的方式发展为AMD的病理特征。 初步数据：(1)CCL2-/-和CCR2-/-小鼠随着年龄的增长出现脂褐素、玻璃体、地理萎缩和脉络膜新生血管(CNV)。(2)随着年龄的增长，两种基因敲除株的视网膜色素上皮(RPE)和脉络膜中均有补体C5和Ig G沉积，与AMD患者一样。(3)这些发现在年龄匹配的野生型小鼠中不存在。(4)老龄野生型小鼠脉络膜有巨噬细胞渗入，但未见大量敲除。(5)C5a和Ig G可上调CCL2的RPE分泌。(6)C5a和Ig G上调RPE和脉络膜内皮细胞分泌血管内皮生长因子(VEGF)，与CNV的发生发展一致。(7)巨噬细胞被C5a和Ig G固定并黏附。 假说：(1)CCL2-/-或CCR2-/-小鼠体内与衰老相关的红斑狼疮和脂褐素的积累是由于清道夫巨噬细胞的清除受损，在缺乏CCL2或其受体CCR2的情况下，清道夫巨噬细胞的募集受到损害，最终导致地理萎缩和CNV。(2)修复CCL2或CCR2功能可预防或逆转基因敲除小鼠的AMD样病理改变。 具体目标：(1)通过检眼镜、血管造影术和组织病理学，与年龄匹配的野生型小鼠比较，量化CCL2-/-或CCR2-/-小鼠的AMD样特征的发展。(2)证明CCL2-/-或CCR2-/-衰老小鼠视网膜色素上皮和脉络膜中发现的蛋白质沉积可刺激CCL2和血管内皮生长因子的产生，并且巨噬细胞黏附和降解这些蛋白质沉积。(3)证实CCL2或CCR2功能的挽救可抑制或逆转老年CCL2-/-或CCR2-/-小鼠的AMD样病理改变。 意义：这些研究将为AMD提供机械性见解和更有效的治疗方法。

项目成果

Modulation of angiogenesis by a tetrameric tripeptide that antagonizes vascular endothelial growth factor receptor 1.

通过拮抗血管内皮生长因子受体 1 的四聚体三肽调节血管生成。

• DOI: 10.1074/jbc.m806607200
• 发表时间: 2008
• 期刊: The Journal of biological chemistry
• 作者: Ponticelli,Salvatore;Marasco,Daniela;Tarallo,Valeria;Albuquerque,RomuloJC;Mitola,Stefania;Takeda,Atsunobu;Stassen,Jean-Marie;Presta,Marco;Ambati,Jayakrishna;Ruvo,Menotti;DeFalco,Sandro
• 通讯作者: DeFalco,Sandro

Fifty years later: the disk goes to the prom.

• DOI: 10.1172/jci36515
• 发表时间: 2008-08
• 期刊: The Journal of clinical investigation
• 作者: M. Kleinman;J. Ambati