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: 7665338
• 负责人: Andrius Kazlauskas
• 金额: $ 48.13万
• 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/7665338
• 关键词: 1-Phosphatidylinositol 4-Kinase; Age related macular degeneration; Alleles; Biological Assay; Blood Vessels; Child; Coculture Techniques; Cornea; Data; Dependence; Development; Disease; Employee Strikes; Enzymes; Event; Exudative age-related macular degeneration; 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; effective therapy; in vitro Model; in vivo; insight; middle age; next generation; novel; prevent; proliferative diabetic retinopathy; therapeutic angiogenesis; therapy development; vascular bed; vessel regression

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（由申请人提供）：血管生成是许多眼部疾病的基本病理成分，遭受了世界人群的大部分。在我们对促进血管生成的因素的理解中，已经取得了重大进展。这导致了有效的疗法，以防止形成新的血管。由于许多患者患有现有的病理血管，因此诱导血管消退的药物将非常有用。开发这种疗法的主要障碍是我们对在分子水平上如何控制血管稳定性和回归的理解不足。 长期目标是阐明控制血管稳定性和回归的分子机制。我们的发现将使下一代疗法的发展逆转基于血管生成的眼部疾病，例如ROP，PDR和AMD的湿形式。通过研究如何调节现有血管的稳定性和回归，该赠款将对血管生成领域做出独特而互补的贡献，该领域主要集中在血管形成上。 中心假设是信号酶控制现有血管的命运。更具体地说，磷酸肌醇3激酶（PI3K）活性的振幅控制血管稳定性。一旦血管不稳定，则通过诱导可溶性回归因子的产生来触发磷脂酶C Y（PLCY）触发回归。我们将在以下一组目标中检验这一假设。 1。研究PI3K在治理船舶稳定性中的作用。我们将测试PI3K/AKT输出的大小是否是管稳定性的关键决定因素。使用单单和共培养模型，我们将在稳定和不稳定的管子中比较PI3K/AKT输出。此外，我们将确定强迫PI3K/AKT输出的变化是否会导致稳定性的相应变化。 2。确定PLCY如何触发血管回归。我们已经建立了检测回归因子的测定法，并确定了出色的候选者：自动赛（ATX）。我们将确定AT​​X表达的时机，是否必要和/或足以进行回归及其对PLCY的依赖。这些研究将检验我们的工作假设，即通过促进可溶性回归因子的分泌来触发回归。 3。确定PLCY和ATX对体内稳定性和回归的重要性（小鼠）。这个目标的工作假设是，体外环境中稳定性和回归的调节因子也将在体内发挥作用。该假设将通过比较野生型眼睛和小鼠杂合子的稳定性和血管的稳定性和血管的稳定性和回归来检验。