VEGFR2 Modulates Corneal Angiogenesis and Lymphangiogenesis

描述（由申请人提供）：角膜新生血管（NV）是一种常见的致残性疾病，是角膜损伤或感染后致盲的主要原因。我们的长期目标是表征VEGF受体在角膜中央血管生成（VA）和淋巴管生成（LA）两个过程中的作用。上皮可溶性形式的VEGFR-2 （sVEGFR-2）在LA中的参与已被很好地表征。然而，膜结合血管VEGFR-2 （mbVEGFR-2）在角膜VA和LA中的作用尚不清楚。这些拟议的实验旨在表征VEGFR-2的膜结合异构体的潜在血管生成和淋巴管生成作用。我们提出假设，血管mbVEGFR2可能具有不同的作用，与VEGFR1或VEGFR3不同，在响应VEGF-A（向VA）或VEGF-C（向LA）诱导角膜血管生成/淋巴管生成。已经提出了两个特定的目的来表征VEGFR- 2在角膜血管生成和淋巴管生成中的作用。目的a：使用诱导的条件敲除小鼠系来确定mbVEGFR2是否在角膜中与sVEGFR1和sVEGFR2保持平衡关系。目的b：表征促血管生成药物对VEGFR活性和VA/LA起始、进展和维持的个体作用。意义：内皮受体mbVEGFR2位于VA/LA起始的十字路口。我们提出的研究策略将明确mbVEGFR2在维持正常和受伤眼睛角膜边界血管/无血管平衡中的作用，增加我们对VEGFR2-R3关系的理解，并分离促血管生成剂和mbVEGFR2在增殖、迁移和管形成中的相对贡献。更好地了解这种受体在正常和受伤眼睛中的作用具有重要的临床意义，因为它增加了我们开发治疗方法的能力，以防止或逆转角膜、其他移植手术以及肿瘤生长和转移中的病理性VA和LA。

DESCRIPTION (provided by applicant): Corneal neovascularization (NV) is a common, disabling condition and a major cause of blindness that can follow corneal injury or infection. Our long term goal is to characterize the role of VEGF receptors in the two central corneal vascularization processes, vascular angiogenesis (VA) and lymphangiogenesis (LA). The involvement of the epithelial, soluble form of VEGFR-2 (sVEGFR-2) in LA has been well characterized. However, the role of membrane- bound, vascular VEGFR-2 (mbVEGFR-2) in corneal VA and LA has not. These proposed experiments are designed to characterize the potential angiogenic and lymphangiogenic roles of the membrane bound isoform of VEGFR-2. We propose the hypothesis that vascular mbVEGFR2 may have distinct roles, separate from those of VEGFR1 or VEGFR3, in response to induction by VEGF-A (towards VA) or VEGF-C (towards LA) in corneal angiogenesis/ lymphangiogenesis. Two specific aims have been proposed to characterize the role of VEGFR- 2 in corneal angiogenesis and lymphangiogenesis. Aim A. Use inducible, conditional knockout mouse lines to determine whether mbVEGFR2 maintains a counterbalanced relationship with sVEGFR1 and sVEGFR2 in the cornea. Aim B. Characterize the individual roles of pro- angiogenic agents on VEGFR activity and VA/LA initiation, progression, and maintenance. SIGNIFICANCE: The endothelial receptor mbVEGFR2 sits at the crossroads of VA/LA initiation. Our proposed research strategy will define the role mbVEGFR2 plays in maintaining the vascular/avascular balance at the corneal border in both the normal and injured eye, increase our understanding of the VEGFR2-R3 relationship, and separate the relative contributions of pro-angiogenic agents and mbVEGFR2 to proliferation, migration, and tube formation. A better understanding of the role this receptor plays in both the normal and injured eye is of clinical importance because it increases our ability to develop therapeutic methods to prevent or reverse pathological VA and LA in the cornea, in other transplant procedures, and in tumor growth and metastasis.