Bcl-2, Subretinal Scar Formation and Neovascular AMD

项目摘要 视网膜相关性黄斑变性（AMD）是一种进行性神经退行性疾病， 通常超过60岁的个体导致视力丧失。炎症越来越被认为是一种 在新生血管形成中，驱动脉络膜新生血管（CNV）和视网膜下瘢痕形成的重要调节剂 AMD（nAMD）。尽管人们在如何抑制CNV方面付出了很大的努力，但所知甚少 关于纤维化和视网膜下疤痕的开始和持续。不幸的是，至少1/3的nAMD 患者出现视网膜下瘢痕，这通常与不成功的抗VEGF治疗相关 结果。炎症、纤维化、CNV及其终止与过程之间的相互关系 涉及的范围并不明确。我们已经证明了Bcl-2家族成员在这些过程中发挥的重要作用。 Bcl-2是抗凋亡Bcl-2家族成员，抑制炎症。 单核巨噬细胞（MP）发挥作用 在脉络膜炎症、新生血管形成和视网膜下瘢痕形成中起重要作用。我们的假设是 MP炎症中Bcl-2的过度表达导致视网膜下纤维化的增强， 和疤痕形成。通过增加Bcl-2表达延长细胞寿命， 对组织内稳态的负面影响。在本提案中，我们将采取创新的方法， MP中Bcl-2表达是否维持导致CNV、视网膜下纤维化和瘢痕形成的炎症。 此外，我们将利用几种方法来阻断Bcl-2功能并增加凋亡，包括： FDA批准了维奈托克（ABT-199），已成功用于治疗癌症。提出的目标 本研究将确定MP中Bcl-2的表达在多大程度上导致了持续性纤维化和视网膜下瘢痕 激光光凝介导的CNV形成。我们将研究它对炎症，CNV， 当用Bcl-2抑制剂治疗时，视网膜下纤维化和瘢痕形成和消退，例如FDA 批准ABT-199。描述Bcl-2在调节炎症和随后的炎症反应中的基本作用。 纤维化和视网膜下瘢痕形成的改善将允许极大地改善患有nAMD的患者的视力结果。

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.