The Role of Neuroprotectin D1 in Choroidal Neovascularization

神经保护素 D1 在脉络膜新生血管形成中的作用

• 批准号: 8257948
• 负责人: Kristopher Graye Sheets
• 金额: $ 1.01万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-07-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257948
• 关键词: Accounting; Affect; Age; Age related macular degeneration; Agonist; Angiogenesis Inhibitors; Angiogenic Factor; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Atrophic; Attenuated; Blindness; Blood; Blood Vessels; Boxing; Cartoons; Cell Survival; Cells; Choroidal Neovascularization; Complex; Disease; Docosahexaenoic Acids; Equilibrium; Experimental Models; Extravasation; Exudative age-related macular degeneration; Eye diseases; Fatty Acids; Gene Expression; Growth; Growth Factor; Homeostasis; Human; Impairment; Inflammatory; Injection of therapeutic agent; Laboratories; Lasers; Liquid substance; Mediator of activation protein; Modeling; Outcome Study; Oxidative Stress; Oxygen; Pathologic Neovascularization; Pathology; Phagocytosis; Photoreceptors; Recycling; Research Project Grants; Research Training; Retinal; Retinal Diseases; Retinal Neovascularization; Role; Signal Transduction; Structure of retinal pigment epithelium; System; Testing; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; angiogenesis; base; cost; lipid mediator; neuroprotectin D1; neurotrophic factor; novel; overexpression; pigment epithelium-derived factor; prevent; public health relevance; receptor; research study; response; retinal angiogenesis

DESCRIPTION (provided by applicant): Neovascular age-related macular degeneration (AMD), accounts for more than 85% of lost vision and involves abnormal retinal pigment epithelium (RPE), choroidal neovascularization (CNV), and photoreceptor atrophy. This research project focuses on novel cell signaling involved in pathological angiogenesis associated with neovascular AMD. We propose to study neuroprotectin Dl (NPD1), a novel stereospecific lipid mediator that displays potent anti-inflammatory actions and neuroprotective bioactivity (20,25). NPD1 is a derivative of docosahexaenoic acid(20). This fatty acid is actively recycled by RPE to, and highly enriched in, photoreceptor outer segments (16). Human RPE cells synthesize NPD1 in response to oxidative stress(24), photoreceptor outer segment phagocytosis(24), and neurotrophic factors(23). The anti-angiogenic growth factor pigment epithelium-derived factor (PEDF) is the most potent neurotrophic factor agonist for NPD1 synthesis(23). Our central hypothesis is that NPD1, a modulator of pro-inflammatory gene expression and cell survival, ameliorate CNV. Normal vasculature is regulated by pro- and anti-angiogenic factors. AMD shifts this homeostatic balance in favor of pro-angiogenic factors, resulting in choroidal neovascularization that disturbs the RPE-photoreceptor complex(36). PEDF has been shown to inhibit CNV(1,21,22) and we have demonstrated that PEDF selectively activates the synthesis of NPD1(23). Therefore, NPD1 may be a key mediator in the anti-angiogenic actions of PEDF. We propose to test the specific aims that (1) NPD1 inhibits CNV, (2) NPD1 modulates angiogenic signaling in CNV, and (3) NPD1 participates in PEDF's inhibition of CNV. Public Health Relevance: This project will elucidate inherent protective mechanisms against age-related macular degeneration and other blinding eye diseases that involve leakage of blood and fluids from uncontrolled blood vessel growth. The outcomes from this study could provide the basis of highly effective low-cost therapies for age-related macular degeneration.

描述（由申请人提供）：与新血管相关的黄斑变性（AMD），占视力丧失的85％以上，涉及视网膜色素上皮异常（RPE），脉络膜新生血管形成（CNV）和光感受器的萎缩。该研究项目的重点是与新生血管AMD相关的病理血管生成涉及的新细胞信号传导。我们建议研究神经保护素DL（NPD1），这是一种新型的立体型脂质介质，显示出有效的抗炎作用和神经保护性生物活性（20,25）。 NPD1是Docosahexaenoic酸的衍生物（20）。这种脂肪酸通过RPE积极回收，并高度富集感光细胞外部段（16）。人类RPE细胞响应氧化应激（24），感光细胞外部段吞噬作用（24）和神经营养因子（23）而合成NPD1（24）。抗血管生成因子色素上皮因子（PEDF）是NPD1合成的最有效的神经营养因子激动剂（23）。我们的中心假设是NPD1是促炎基因表达和细胞存活的调节剂，改善CNV。正常的脉管系统受促抗血管生成因子的调节。 AMD改变了这种体内平衡，而有利于促血管生成因素，导致脉络膜新生血管形成破坏RPE photoreceptor络合物（36）。 PEDF已显示出抑制CNV（1,21,22），我们已经证明PEDF有选择地激活NPD1的合成（23）。因此，NPD1可能是PEDF抗血管生成作用的关键介体。我们建议测试（1）NPD1抑制CNV，（2）NPD1调节CNV中的血管生成信号传导，（3）NPD1参与PEDF的CNV抑制。公共卫生相关性：该项目将阐明针对年龄相关的黄斑变性和其他盲目的眼部疾病的固有保护机制，涉及血液和流体流体泄漏从不受控制的血管生长中泄漏。这项研究的结果可以为与年龄相关的黄斑变性提供高效的低成本疗法的基础。

项目成果

Neuroprotectin D1 attenuates laser-induced choroidal neovascularization in mouse.

Neuroprotectin D1 可减弱小鼠激光诱导的脉络膜新生血管形成。

• 发表时间: 2010
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Sheets,KristopherG;Zhou,Yongdong;Ertel,MonicaK;Knott,EricJ;ReganJr,CorneliusE;Elison,JasmineR;Gordon,WilliamC;Gjorstrup,Per;Bazan,NicolasG
• 通讯作者: Bazan,NicolasG