VEGF Antagonism and Resistance to Neovascular AMD

VEGF 拮抗和抗新生血管性 AMD

基本信息

批准号：
10557167
负责人：
CHRISTINE M SORENSON
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557167
关键词：
Affect Age Age related macular degeneration Aging Alleles American Anti-Inflammatory Agents Apoptotic Asian ancestry Atrophic BCL2 gene BCL2L11 gene BH3 Domain Biological Markers Blindness Blood Vessels Bruch&apos s basal membrane structure Cell physiology Cessation of life Choroidal Neovascularization Degenerative Disorder Development East Asian Emotional Endophthalmitis Endothelial Cells Exudative age-related macular degeneration Eye Eye diseases Family member Genetic Polymorphism Genetic Variation Goals Hispanic ancestry Homeostasis Human In Vitro Individual Inflammation Inflammatory Injections Liquid substance Macrophage Mediating Modality Mus Nucleotides Outcome Pathogenesis Patients Permeability Play Population Process Progressive Disease Property Resistance Retina Retinal Degeneration Risk Role Rupture Savings Single Nucleotide Polymorphism Structure of retinal pigment epithelium Testing Therapeutic Treatment Efficacy Treatment Factor Treatment Failure Vascular Endothelial Growth Factors Vascular Permeabilities Vision Visual antagonist cancer therapy comparative efficacy diagnostic assay dosage in vivo Model innovation intravitreal injection laser photocoagulation mast cell neovascularization neurovascular recruit response restraint standard care standard of care success treatment choice

项目摘要

PROJECT SUMMARY Neovascularization is a hallmark of many ocular diseases including age-related macular degeneration (AMD). AMD is a progressive and degenerative disease that affects individuals typically over the age of 60 leading to vision loss. The proangiogenic activity of VEGF contributes to the pathogenesis of neovascular AMD (nAMD). Thus, the treatment of choice for nAMD is intravitreal administration of anti-VEGF. Unfortunately, for unknown reasons a significant number of patients have poor to no response with anti-VEGF therapy for nAMD. Since anti-VEGF therapy comes with increased treatment burden and risk of vision complications including retinal atrophy and endophthalmitis, identifying patients likely to respond prior to the onset of treatment is beneficial. Our hypothesis is that Bim, a pro-apoptotic Bcl-2 family member, restrains VEGF-driven inflammation and choroidal neovascularization (CNV). In this proposal we will take the innovative approach of determining whether genetic variation in Bim expression is responsible for anti-VEGF therapy failure for nAMD. The aims proposed here will determine whether Bim expression is required for anti-VEGF treatment to normalize endothelial cell permeability and proangiogenic properties. We will test the hypothesis that Bim expression is needed for the efficacy of anti-VEGF treatment of nAMD and determine whether Bim single nucleotide polymorphisms (SNPs) modulate the efficacy of anti-VEGF treatment. Together these studies will give us a unique perspective as to whether Bim polymorphisms impede the success of anti-VEGF therapy for nAMD. Thus, development of a biomarker will alleviate the treatment burden and potential vision risks associated with anti-VEGF therapy if no beneficial outcome will be obtained.

项目摘要新血管形成是许多眼部疾病的标志，包括与年龄相关的黄斑变性（AMD）。 AMD是一种进行性和退化性疾病，通常会影响60岁以上的个体，导致视力丧失。 VEGF的促血管生成活性有助于新血管AMD（NAMD）的发病机理。因此，NAMD选择的治疗方法是玻璃体内给药。不幸的是，对于未知原因很大一量的患者对NAMD的抗VEGF疗法的反应很差。自从抗VEGF疗法带来了增加的治疗负担和视力并发症的风险萎缩和内嗜性，确定可能在治疗发作之前反应的患者是有益的。我们的假设是BIM是一种促凋亡的Bcl-2家族成员，限制了VEGF驱动的炎症和脉络膜新生血管形成（CNV）。在此提案中，我们将采取创新的方法确定BIM表达中的遗传变异是否导致NAMD的抗VEGF治疗失败。此处提出的目的将确定是否需要抗VEGF治疗的BIM表达标准化内皮细胞的渗透性和促血管生成特性。我们将测试BIM的假设需要表达抗VEGF治疗NAMD的功效，并确定BIM是否单一核苷酸多态性（SNP）调节抗VEGF治疗的功效。这些研究将共同关于BIM多态性是否阻碍了抗VEGF疗法的成功，给我们一个独特的观点 namd。因此，生物标志物的开发将减轻治疗负担和潜在的视力风险如果未获得有益结果，则与抗VEGF治疗相关。