Signaling events that control the fate of existing vessels

控制现有船只命运的信号事件

• 批准号: 7477503
• 负责人: Andrius Kazlauskas
• 金额: $ 47.16万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477503
• 关键词: 1-Phosphatidylinositol 4-Kinase; Age related macular degeneration; Alleles; Biological Assay; Blood Vessels; Child; Coculture Techniques; Cornea; Data; Dependence; Development; Disease; Disease regression; Employee Strikes; Enzymes; Event; Eye; Foundations; Goals; Grant; In Vitro; Modeling; Molecular; Mono-S; Mus; Outcome Study; Output; Pathologic Neovascularization; Patients; Phosphatidylinositols; Phospholipase C; Phosphotransferases; Play; Population; Production; Retinopathy of Prematurity; Role; Scientific Advances and Accomplishments; Signal Transduction; Testing; Time; Tube; Wild Type Mouse; Work; aged; angiogenesis; antiangiogenesis therapy; base; in vitro Model; in vivo; insight; middle age; next generation; novel; prevent; proliferative diabetic retinopathy; therapeutic angiogenesis; vascular bed

DESCRIPTION (provided by applicant): Angiogenesis is an essential pathological component of numerous ocular diseases that afflicts a large segment of the world's population. Substantial advances have been made in our understanding of the factors that promote angiogenesis. This has led to effective therapies that prevent the formation of new blood vessels. Since many patients have existing pathological blood vessels, agents that induce regression of vessels would be very useful. The major barrier to developing such therapies is our lack of understanding of how vessel stability and regression is controlled at the molecular level. The long-term goal is to elucidate the molecular mechanisms controlling vessel stability and regression. Our findings will enable the development of next generation therapies that reverse angiogenic-based ocular diseases such as ROP, PDR and the wet form of AMD. By studying what regulates the stability and regression of existing vessels, this grant will make a unique and complementary contribution to the field of angiogenesis, which is largely focused on the formation of vessels. The central hypothesis is that signaling enzymes control the fate of existing vessels. More specifically, the amplitude of phosphoinositide 3 kinase (PI3K) activity governs vessel stability. Once vessels are destabilized, then phospholipase C y (PLCy) triggers regression by inducing the production of a soluble regression factor. We will test this hypothesis in the following set of aims. 1. Investigate the role of PI3K in governing vessel stability. We will test whether the magnitude of the PI3K/Akt output is a key determinant of tube stability. Using both mono- and co-culture models, we will compare PI3K/Akt output in stable and unstable tubes. In addition, we will determine whether forcing a change in the PI3K/Akt output results in a corresponding change in stability. 2. Determine how PLCy triggers vessel regression. We have established assays to detect regression factors and identified an excellent candidate: autotaxin (ATX). We will determine the timing of ATX expression, whether it's necessary and/or sufficient for regression, and its dependence on PLCy. These studies will test our working hypothesis that PLCy triggers regression by promoting the secretion of a soluble regression factor. 3. Determine the importance of PLCy and ATX for stability and regression in vivo (mice). The working hypothesis for this aim is that the regulators of stability and regression in the in vitro setting will also play a role in vivo. This hypothesis will be tested by comparing stability and regression of vessels in several vascular beds within eyes of wild type and mice heterozygous for PLCy or ATX.

描述(申请人提供)：血管生成是许多眼科疾病的基本病理成分，这些疾病困扰着世界上很大一部分人口。我们对促进血管生成的因素的理解已经取得了实质性的进展。这导致了防止新血管形成的有效疗法。由于许多患者存在病理性血管，导致血管退行性变的药物将非常有用。开发这种疗法的主要障碍是我们缺乏对如何在分子水平上控制血管稳定性和退行性的了解。 长期目标是阐明控制血管稳定性和退行性的分子机制。我们的发现将有助于开发下一代疗法，逆转基于血管生成的眼部疾病，如ROP、PDR和湿性AMD。通过研究是什么调节现有血管的稳定性和退行性，这项资助将对血管生成领域做出独特和补充的贡献，该领域主要关注血管的形成。 核心假设是，信号酶控制着现有血管的命运。更具体地说，磷脂酰肌醇3激酶(PI3K)活性的幅度决定着血管的稳定性。一旦血管不稳定，则磷脂酶Cy(PLCy)通过诱导产生一种可溶性回归因子来触发回归。我们将在下面的一组目标中测试这一假设。 1.研究PI3K在调节血管稳定性中的作用。我们将测试PI3K/Akt输出的大小是否是管道稳定性的关键决定因素。使用单一培养和共培养模型，我们将比较稳定和不稳定管中PI3K/Akt的产量。此外，我们将确定强制更改PI3K/Akt输出是否会导致相应的稳定性变化。 2.确定PLCy如何触发血管回归。我们已经建立了检测回归因素的分析方法，并确定了一个很好的候选因素：自体趋化蛋白(ATX)。我们将确定ATX表达的时间，它对回归是否必要和/或充分，以及它对PLCy的依赖。这些研究将检验我们的工作假设，即PLCy通过促进可溶回归因子的分泌来触发回归。 3.确定PLCy和ATX对体内(小鼠)稳定性和消退的重要性。这一目标的工作假设是，在体外环境中稳定和回归的调节器也将在体内发挥作用。这一假设将通过比较野生型和PLCy或ATX杂合子小鼠眼睛内几个血管床上血管的稳定性和退行性来检验。