Targeting survival factors for ocular neovascularization

描述：参与新生血管形成（NV）的血管内皮细胞依赖于存活因子。如果生存因子被撤回或阻断，内皮细胞发生凋亡，NV消退。 因此，确定生存因素并找到阻断它们的方法是开发已建立的NV治疗的有用策略。就在萌芽之后，大多数类型的NV倾向于非常依赖于血管内皮生长因子（VEGF）来存活，但是随着时间的推移，血管成熟，并且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）获得额外的存活信号。定义这些生存信号是一个重要的目标。两种候选物是通过内皮细胞上的Tie受体起作用的血管生成素1（Ang 1）和通过周细胞上的PDGF β受体起作用的血小板衍生生长因子-B（PDGF-B）。与新生血管相比，完全成熟的血管倾向于较少依赖于VEGF、Ang 1和PDGF-B，但这是一个相对差异。例如，成人中的一些正常血管床，通常包含有孔血管的那些血管床，仍然包含当VEGF被阻断时退化的血管。此外，虽然这些分子主要靶向血管细胞，但它们也可能对某些神经元具有促进存活的作用。因此，为了靶向这些存活信号以开发眼部NV的治疗，关键是确定阻断它们对正常视网膜和脉络膜以及眼部NV的影响。我们建议使用转基因小鼠来实现这一点，所述转基因小鼠具有针对每种存活信号的有效阻断剂的诱导表达;可溶性VEGF受体1与IgG Fc偶联（VEGFtrap）以阻断VEGF，Ang 2以阻断Ang 1，以及可溶性PDGF β受体与IgG Fc偶联（PDGFtrap）以阻断PDGF-B。单独和一起表达这些拮抗剂中的每一种的效果将在以下两个方面进行检查： 在正常视网膜和脉络膜上存在了不同时间量的脉络膜NV。 巨噬细胞是NV的存活和死亡信号的另一个丰富来源;因此，我们将使用其中巨噬细胞被消融的小鼠来确定它们在VEGF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，因为它可能导致新的治疗方法，用于治疗发生在年龄相关性黄斑变性和糖尿病视网膜病变中的已建立的眼部NV，这是美国严重视力丧失的最常见原因。

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 If the survival factors are withdrawn or blocked, the endothelial cells undergo apoptosis and the NV regresses.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.