Bcl-2, Subretinal Scar Formation and Neovascular AMD

Bcl-2、视网膜下疤痕形成和新生血管性 AMD

• 批准号: 10733960
• 负责人: CHRISTINE M SORENSON
• 金额: $ 42.76万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733960
• 关键词: Affect; Age; Age related macular degeneration; Apoptosis; Apoptotic; Automobile Driving; BCL2 gene; Blindness; Blood Vessels; Bruch' s basal membrane structure; Cells; Cessation of life; Choroidal Neovascularization; Cicatrix; Elderly; Exudative age-related macular degeneration; FDA approved; Family member; Fibrosis; Functional disorder; Goals; Homeostasis; Individual; Inflammation; Intervention; Link; Longevity; Malignant Neoplasms; Mediating; Modality; Mononuclear; Neurodegenerative Disorders; Outcome; Pathogenesis; Patient-Focused Outcomes; Patients; Phagocytes; Play; Process; Progressive Disease; Resolution; Role; Rupture; Structure of retinal pigment epithelium; Testing; Tissues; Treatment outcome; Vision; Visual; Visual impairment; aging population; antifibrotic treatment; bevacizumab; improved; inhibitor; innovation; laser photocoagulation; member; membrane model; mouse model; neovascularization; new growth; novel; photoreceptor degeneration; prevent

PROJECT SUMMARY Age-related macular degeneration (AMD) is a progressive and neurodegenerative disease that affects individuals typically over the age of 60 leading to vision loss. Inflammation is increasingly recognized as an important modulator driving choroidal neovascularization (CNV) and subretinal scar formation in neovascular AMD (nAMD). Although great effort has been given to understanding how to curtail CNV, less is known regarding the initiation and persistence of fibrosis and subretinal scars. Unfortunately, at least 1/3 of nAMD patients develop subretinal scars, which are typically associated with unsuccessful anti-VEGF treatment outcomes. The interrelationship between inflammation, fibrosis, CNV, their termination and the processes involved is not well defined. We have shown the important role Bcl-2 family members play in these processes. Bcl-2 is an anti-apoptotic Bcl-2 family member that prolongs inflammation. Mononuclear phagocytes (MP) play essential roles in choroidal inflammation, neovascularization, and subretinal scar formation. Our hypothesis is that unbridled Bcl-2 expression in MP prolongs inflammation resulting in enhanced subretinal fibrosis and scar formation. Extending cell lifespan, through increased Bcl-2 expression, has a well-documented negative impact on tissue homeostasis. In this proposal we will take the innovative approach of determining whether Bcl-2 expression in MP sustains inflammation leading to CNV, subretinal fibrosis and scar formation. Furthermore, we will utilize several approaches to block Bcl-2 function and increase apoptosis including the FDA approved Venetoclax (ABT-199), which has been successfully used to treat cancer. The aims proposed here will determine the extent to which Bcl-2 expression in MP drives persistent fibrosis and subretinal scar formation following laser photocoagulation mediated CNV. We will examine its impact on inflammation, CNV, subretinal fibrosis and scar formation and regression when treated with Bcl-2 inhibitors, such as the FDA approved ABT-199. Delineating the fundamental role Bcl-2 plays in modulating inflammation and subsequent fibrosis and subretinal scar formation will allow to greatly improve vision outcomes in patients with nAMD.

项目摘要 与年龄相关的黄斑变性（AMD）是一种进行性和神经退行性疾病，影响 个人通常60岁以上导致视力丧失。炎症越来越被认为是 重要的调节剂驱动脉络膜新生血管形成（CNV）和视网膜下疤痕形成 AMD（NAMD）。尽管为了解如何减少CNV而付出了巨大的努力，但已知较少 关于纤维化和视网膜下疤痕的启动和持久性。不幸的是，至少1/3的NAMD 患者会出现视网膜下疤痕，通常与失败的抗VEGF治疗有关 结果。炎症，纤维化，CNV，终止和过程之间的相互关系 涉及的定义不当。我们已经展示了BCL-2家庭成员在这些过程中所扮演的重要作用。 BCL-2是延长炎症的抗凋亡BCL-2家族成员。 单核吞噬细胞（MP） 在脉络膜炎症，新血管形成和视网膜下疤痕形成中的重要作用。我们的假设是 在MP中，无限制的Bcl-2表达延长了炎症，导致视网膜下纤维化增强 和疤痕形成。通过增加的Bcl-2表达，延长细胞寿命有据可查 对组织稳态的负面影响。在此提案中，我们将采取创新的方法来确定 MP中的Bcl-2表达是否会导致CNV，视网膜下纤维化和疤痕形成。 此外，我们将利用几种方法来阻止Bcl-2功能并增加凋亡 FDA批准了Venetoclax（ABT-199），该毒素已成功用于治疗癌症。提出的目的 这里将确定MP中BCl-2表达的程度驱动持续性纤维化和视网膜下疤痕 激光光凝后介导的CNV后形成。我们将研究其对炎症的影响，CNV， 用Bcl-2抑制剂（例如FDA）处理后，视网膜下纤维化和疤痕形成和回归 批准的ABT-199。描述Bcl-2在调节炎症和随后的调节中发挥的基本作用 纤维化和视网膜下疤痕形成将大大改善NAMD患者的视力结局。