Targeting survival factors for ocular neovascularization

描述：血管内皮细胞参与新生血管(NV)依赖于生存因素。如果生存因素被取消或阻断，内皮细胞就会发生凋亡，NV就会消退。因此，确定生存因素并找到阻止它们的方法是开发已建立的新城疫治疗方法的有用策略。大多数类型的NV在萌芽后往往非常依赖血管内皮生长因子(VEGF)生存，但随着时间的推移，血管成熟，作为成熟过程的一部分，它们从细胞外基质(ECM)和血管周围细胞(周细胞)获得额外的生存信号。定义这些生存信号是一个重要的目标。两个候选基因分别是血管生成素1(Ang1)和血小板衍生生长因子B(PDGF-B)，前者通过Tie受体作用于内皮细胞，后者通过PDGFβ受体作用于周细胞。与新血管相比，完全成熟的血管对VEGF、Ang1和PDGF-B的依赖程度较低，但这是一个相对的差异。例如，成人的一些正常血管床，通常是那些包含有开窗血管的血管床，仍然包含当血管内皮生长因子被阻断时会退缩的血管。此外，虽然这些分子主要针对血管细胞，但它们也可能对一些神经元具有促进存活的作用。因此，为了针对这些存活信号开发眼部NV的治疗方法，确定阻断它们对正常视网膜和脉络膜以及眼NV的影响是至关重要的。我们建议使用转基因小鼠来实现这一点，转基因小鼠的每个生存信号都可以诱导表达有效的阻断剂；可溶性血管内皮生长因子受体1偶联到免疫球蛋白Fc(VEGFtrap)来阻断血管内皮生长因子，血管紧张素2来阻断血管紧张素转换酶1，以及可溶性PDGFβ受体偶联到免疫球蛋白抗体Fc(PDGFtrap)来阻断PDGF-B。单独和共同表达这些拮抗剂的效果将在两种情况下进行检验 脉络膜NV已经存在了不同的时间，在正常的视网膜和脉络膜上。 巨噬细胞是NV的另一个丰富的生存和死亡信号来源；因此，我们将使用去除巨噬细胞的小鼠来确定它们在血管内皮生长因子诱导的眼部NV的形成和消退中的作用。这项研究解决了重要的公共卫生问题，因为它可能导致已建立的眼部NV的新疗法，这种NV发生在年龄相关性黄斑变性和糖尿病视网膜病变中，这是美国最常见的严重视力丧失的原因。

DESCRIPTION: Vascular endothelial cells participating in neovascularization (NV) depend upon survival factors. If the survival factors are withdrawn or blocked, the endothelial cells undergo apoptosis and the NV regresses. Thus, identifying survival factors and finding ways to block them is a useful strategy for development of treatments for established NV. Right after sprouting, most types of NV tend to be very dependent upon vascular endothelial growth factor (VEGF) for survival, but over time the vessels mature and as part of the maturation process they acquire additional survival signals from extracellular matrix (ECM) and perivascular cells (pericytes). Defining these survival signals is an important goal. Two candidates are angiopoietin 1 (Ang1) acting through the Tie receptors on endothelial cells and platelet-derived growth factor-B (PDGF-B) acting through PDGF beta receptors on pericytes. Completely mature vessels tend to be less dependent upon VEGF, Ang1, and PDGF-B than new vessels, but this is a relative difference. For instance some normal vascular beds in adults, usually those that contain fenestrated vessels, still contain vessels that regress when VEGF is blocked. Also, while these molecules primarily target vascular cells they may also have survival-promoting effects for some neurons. Therefore, in order to target these survival signals to develop treatments for ocular NV, it is critical to determine the effect of blocking them on the normal retina and choroid as well as on ocular NV. We propose to do this using transgenic mice with inducible expression of potent blockers for each of the survival signals; soluble VEGF receptor 1 coupled to IgG Fc (VEGFtrap) to block VEGF, Ang2 to block Ang1, and soluble PDGF beta receptor coupled to IgG Fc (PDGFtrap) to block PDGF-B. The effect of expressing each of these antagonists alone and together will be examined both on choroidal NV that has been present for various amounts of time, and on the normal retina and choroid. Macrophages are another rich source of both survival and death signals for NV; therefore, we will use mice in which macrophages are ablated to determine their role in formation and regression of VEGF-induced ocular NV. This study addresses important public health problems, because it could lead to new treatments for established ocular NV which occurs in age-related macular degeneration and diabetic retinopathy, the most common causes of severe vision loss in the US.