The Role of Soluble Flt-1 and Raver2 in Ocular Vascular Demarcations

可溶性 Flt-1 和 Raver2 在眼血管分界中的作用

基本信息

  • 批准号:
    8576893
  • 负责人:
  • 金额:
    $ 37.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-05-01 至 2017-07-31
  • 项目状态:
    已结题

项目摘要

Project Abstract Optical transparency in the cornea and retinal photoreceptor layer depends on strict vascular demarcation. This physiologic vascular zoning is compromised in corneal injury and macular degeneration. This project will elucidate the molecular signals, mediators and regulators that sustain ocular vascular compartmentalization, By focusing on the endogenous anti-angiogenic molecule, soluble VEGFR-1 (also known as sFlt-1), and its nuclear up-regulator protein Raver2, in the cornea and the subretinal space. We previously demonstrated that corneal avascularity is dependent on soluble VEGFR-1 (sFlt-1). Morpholinos (synthetic morpholine-based oligonucleotides) upregulating sFlt-1 suppressed suture-induced corneal neovascularization and laser-induced choroidal neovascularization, and improve cornea transplant survival. In exciting new studies, we have discovered that Raver2, an endogenous nuclear regulatory protein, shifts Flt-1 splicing towards the soluble sFlt-1 isoform by modulating RNA processing. This is the first described function of Raver2 and the first identified nuclear promoter of sFlt-1 production. In the retina, we found that sFlt-1 is strongly expressed by the retinal pigment epithelium (RPE) and is vital for photoreceptor avascular privilege. We will build on these findings to characterize the regulation of sFlt-1 and Raver2 in the cornea and the subretinal space. Our central hypotheses are that sFlt-1 is vital to photoreceptor avascular privilege and that Raver2 knockdown will compromise ocular vascular demarcations. Our specific aims are: 1. To determine the molecular regulators of sFlt-1 expression in the cornea and RPE We will identify the nuclear factors that regulate sFlt-1 expression, validate their relevance in angiogenic assays in vivo and in vitro, and identify their RNA binding sequences. We will determine the mechanism of action of Raver2 and whether Pax6, a master regulator of ocular development, binds the Raver2 promoter. 2. To test the prediction that upregulation of sFlt-1 by Raver2 can improve corneal transplant survival and restore photoreceptor avascular privilege in models of AMD We will determine whether Raver2 can improve corneal transplant survival (by reducing corneal neovascularization and associated immune infiltration). Next, we will determine whether Raver2 can increase retinal sFlt-1 and inhibit laser induced choroidal neovascularization. 3. To determine whether genetic ablation of Raver2 induces corneal or choroidal neovascularization. Using available targeted conditonal ES cells (Raver2tm1e(KOMP)Wtsi),we will develop a Raver2 knockout mouse (or Raver2-lox/loxp animal if the knockout is embryonically lethal). We will assess the impact of Raver2 knockout on development of corneal avascularity and retinal vascular demarcations pre- and post-natally, determine the presence of truncated transcripts and expression kinetics of Raver2 in the knockout, and whether Raver2 knockout affects expression of anti- or pro-angiogenic factors
项目摘要 角膜和视网膜感光层的光学透明度取决于严格的血管分界。 这种生理性血管分区在角膜损伤和黄斑变性中受到损害。该项目将 阐明维持眼血管区室化的分子信号、介质和调节剂, 通过关注内源性抗血管生成分子,可溶性VEGFR-1(也称为sFlt-1), 核上调蛋白Raver 2,在角膜和视网膜下腔。 我们以前证明了角膜无血管性依赖于可溶性VEGFR-1(sFlt-1)。 上调sFlt-1的吗啉代(合成的基于吗啉的寡核苷酸)抑制缝合诱导的细胞凋亡。 角膜新生血管和激光诱导的脉络膜新生血管,并改善角膜移植 生存在令人兴奋的新研究中,我们发现Raver 2,一种内源性核调节蛋白, 通过调节RNA加工将Flt-1剪接转向可溶性sFlt-1亚型。这是第一 描述了Raver 2的功能和第一个鉴定的sFlt-1产生的核启动子。在视网膜中, 我们发现sFlt-1在视网膜色素上皮细胞(RPE)中强烈表达,并且对于光感受器至关重要。 无血管特权我们将在这些发现的基础上,描述sFlt-1和Raver 2在肿瘤细胞中的调控。 角膜和视网膜下间隙。我们的中心假设是sFlt-1对于光感受器无血管性 Raver 2的敲除将损害眼血管分界。我们的具体目标是: 1.确定角膜和RPE中sFlt-1表达的分子调控因子 我们将鉴定调节sFlt-1表达的核因子,验证它们在血管生成中的相关性, 在体内和体外测定,并确定其RNA结合序列。我们将确定 Raver 2的作用以及Pax 6(眼发育的主要调节因子)是否结合Raver 2启动子。 2.为了测试Raver 2上调sFlt-1可以改善角膜移植存活率的预测, 在AMD模型中恢复光感受器无血管特权 我们将确定Raver 2是否可以提高角膜移植存活率(通过降低角膜移植存活率)。 新血管形成和相关的免疫浸润)。接下来,我们将确定Raver 2是否可以增加 视网膜sFlt-1和抑制激光诱导的脉络膜新生血管。 3.确定Raver 2基因消融是否诱导角膜或脉络膜新生血管形成。 使用可获得的靶向条件ES细胞(Raver 2 tm 1 e(KOMP)Wtsi),我们将开发Raver 2敲除小鼠(或 Raver 2-lox/loxp动物,如果敲除是胚胎致死的)。我们将评估Raver 2淘汰赛的影响 在出生前和出生后角膜无血管和视网膜血管分界的发展,确定 在敲除中Raver 2的截短转录物和表达动力学的存在,以及Raver 2是否 基因敲除影响抗或促血管生成因子的表达

项目成果

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BALAMURALI K AMBATI其他文献

BALAMURALI K AMBATI的其他文献

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{{ truncateString('BALAMURALI K AMBATI', 18)}}的其他基金

COMP-Ang1: Vascular Normalization and Neuroprotection for Diabetic Retinopathy
COMP-Ang1:糖尿病视网膜病变的血管正常化和神经保护
  • 批准号:
    9004910
  • 财政年份:
    2016
  • 资助金额:
    $ 37.25万
  • 项目类别:
COMP-Ang1: Vascular Normalization and Neuroprotection for Diabetic Retinopathy
COMP-Ang1:糖尿病视网膜病变的血管正常化和神经保护
  • 批准号:
    9197294
  • 财政年份:
    2016
  • 资助金额:
    $ 37.25万
  • 项目类别:
Synergistic OEC-biologic Use for Diabetic Retinal Regeneration
OEC-生物制剂协同用于糖尿病视网膜再生
  • 批准号:
    8820208
  • 财政年份:
    2014
  • 资助金额:
    $ 37.25万
  • 项目类别:
Synergistic OEC-biologic Use for Diabetic Retinal Regeneration
OEC-生物制剂协同用于糖尿病视网膜再生
  • 批准号:
    9040025
  • 财政年份:
    2014
  • 资助金额:
    $ 37.25万
  • 项目类别:
Pre-mRNA Interference of VEGF Pathways in Ocular Angiogenesis
眼部血管生成中 VEGF 通路的前 mRNA 干扰
  • 批准号:
    8391552
  • 财政年份:
    2009
  • 资助金额:
    $ 37.25万
  • 项目类别:
Targeted Morpholino Interference of VEGF Pathways in Ocular Angiogenesis
眼部血管生成中 VEGF 通路的靶向吗啉干扰
  • 批准号:
    8542453
  • 财政年份:
    2009
  • 资助金额:
    $ 37.25万
  • 项目类别:
Pre-mRNA Interference of VEGF Pathways in Ocular Angiogenesis
眼部血管生成中 VEGF 通路的前 mRNA 干扰
  • 批准号:
    7796909
  • 财政年份:
    2009
  • 资助金额:
    $ 37.25万
  • 项目类别:
Sulfated Polysaccharide Derivatives for Treatment of Macular Degeneration
用于治疗黄斑变性的硫酸化多糖衍生物
  • 批准号:
    7745143
  • 财政年份:
    2009
  • 资助金额:
    $ 37.25万
  • 项目类别:
Pre-mRNA Interference of VEGF Pathways in Ocular Angiogenesis
眼部血管生成中 VEGF 通路的前 mRNA 干扰
  • 批准号:
    8195884
  • 财政年份:
    2009
  • 资助金额:
    $ 37.25万
  • 项目类别:
Targeted Morpholino Interference of VEGF Pathways in Ocular Angiogenesis
眼部血管生成中 VEGF 通路的靶向吗啉干扰
  • 批准号:
    8763866
  • 财政年份:
    2009
  • 资助金额:
    $ 37.25万
  • 项目类别:

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