Bcl-2 and ocular neovascularization

Bcl-2 与眼部新生血管形成

基本信息

批准号：
8584292
负责人：
CHRISTINE M SORENSON
金额：
$ 18.44万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584292
关键词：
Address Adult Affect Age related macular degeneration Alleles Angiogenic Factor Apoptosis Attenuated BCL2 gene Blindness Blood Circulation Bronchopulmonary Dysplasia Choroidal Neovascularization Development Diabetic Retinopathy Disease Endothelial Cells Endothelium Epigenetic Process Event Excision Exhibits Exudative age-related macular degeneration Family member Gene Expression Gene Expression Regulation Growth Factor Histone Deacetylase Inhibitor Histones Hypertension Individual Kidney Knockout Mice Lasers Malignant Neoplasms Mediator of activation protein Modality Mus Myocardial Infarction Neoplasms in Vascular Tissue Nephrons Organ Oxygen Pathogenesis Pathway interactions Pericytes Play Premature Infant Prevention Production Protein Acetylation Regimen Retina Retinal Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Risk Role Serum Stroke Supporting Cell Testing Therapeutic Thrombospondin 1 Vascular Endothelial Growth Factors Vision angiogenesis body system critical period effective therapy innovation insight lung development mouse model neoplastic cell neovascular neovascularization nephrogenesis ocular neovascularization overexpression prevent public health relevance response standard of care success therapeutic development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Retinal neovascularization and choroidal neovascularization (CNV), as occur in retinopathy of prematurity (ROP) and age-related macular degeneration (AMD), are major causes of blindness. A significant role for the proangiogenic vascular endothelial growth factor (VEGF) has been established in these diseases. Therefore, intravitreal administration of anti-VEGF has been greatly pursued as treatment for exudative AMD and ROP. However, intravitreal administration of anti-VEGF enters the general circulation resulting in prolonged inhibition of VEGF, which may cause off-target effects including renal thrombotic microangiopathy, myocardial infarction and stroke. Bcl-2 is a key mediator of downstream events in response to both pro- and anti-angiogenic factors, including VEGF and thrombospondin-1 (TSP1). Bcl-2 has been a target of cancer therapeutic regimens due to its ability to selectively disrupt tumor blood vessels and induce apoptosis. Our hypothesis is that inhibition of bcl-2 expression and/or activity will prevent choroidal and retina neovascularization. This hypothesis is supported by our studies showing that VEGF-driven retinal neovascularization requires bcl-2 expression. In addition, removal of a single allele of bc-2 is sufficient to attenuate CNV. In this proposal we take the innovative approach of using bcl-2 antagonists in concert with histone deacetylase (HDAC) inhibitors to selectively prevent ocular neovascularization. Identification of whether bcl-2 expression is essential in endothelial cells and/or perivascular supporting cells for choroidal and retinal neovascularization will give us further insight as to whether both types of neovascularization rely on similar pathways. These studies in combination will give us a unique perspective to identify the most effective treatment strategies to inhibit retinal and choroidal neovascularization and avoid off-target systemic effects.

描述（由申请人提供）：视网膜新血管形成和脉络膜新生血管形成（CNV），如早产（ROP）和与年龄相关的黄斑变性（AMD）所发生的那样，是失明的主要原因。在这些疾病中已经确定了促血管生成血管内皮生长因子（VEGF）的重要作用。因此，玻璃体内抗VEGF的给药已被广泛地作为渗出性AMD和ROP的治疗方法。然而，玻璃体内给药抗VEGF进入一般循环，导致VEGF的长期抑制作用，这可能会导致靶向效果，包括肾脏血栓形成微型病，心肌梗死和中风。 Bcl-2是响应促疾病和抗血管生成因子（包括VEGF和血小板传播-1（TSP1））的下游事件的关键介体（TSP1）。 Bcl-2由于其有选择性破坏肿瘤血管和诱导凋亡的能力，因此一直是癌症治疗方案的靶标。我们的假设是抑制Bcl-2表达和/或活性将预防脉络膜和视网膜新生血管形成。我们的研究表明，VEGF驱动的视网膜新血管形成需要Bcl-2表达，这一假设得到了支持。此外，去除BC-2的单个等位基因足以减弱CNV。在此提案中，我们采用与组蛋白脱乙酰基酶（HDAC）抑制剂一起使用Bcl-2拮抗剂的创新方法，以选择性地预防眼部新生血管化。鉴定Bcl-2表达在内皮细胞和/或血管周围支撑细胞中是否必不可少的脉络膜和视网膜新生血管形成将使我们进一步了解两种类型的新血管形成是否依赖于相似的途径。这些结合的研究将使我们有一个独特的观点，可以确定抑制视网膜和脉络膜新生血管形成的最有效的治疗策略，并避免脱靶的全身效应。