Netrin-1 and Netrin-1 Preconditioned EPCs in Vascular Protection

Netrin-1 和 Netrin-1 预处理 EPC 在血管保护中的作用

• 批准号: 10132380
• 负责人: Hua Linda Cai
• 金额: $ 45.86万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132380
• 关键词: Address; Angioplasty; Apolipoprotein E; Apoptosis; Atherosclerosis; Attenuated; Blood Vessels; Clinical; Cyclic GMP; Dependence; Development; Dyslipidemias; Endothelium; Fatty acid glycerol esters; Homing; Infiltration; Injury; Intervention; Knockout Mice; Lead; Mediating; MicroRNAs; Molecular; Mus; Mutation; NTN1 gene; Oxidants; Oxidative Stress; Pathology; Pathway interactions; Phosphotransferases; Physiological; Procedures; Role; Signal Pathway; Signal Transduction; attenuation; blood vessel occlusion; conditioning; design; endothelial stem cell; feeding; femoral artery; in vivo; innovation; macrophage; migration; monocyte; netrin receptor; novel; novel therapeutic intervention; novel therapeutics; preconditioning; protective effect; restenosis; stem cell function; stem cell survival

ABSTRACT The application aims to identify potential roles and molecular mechanisms of netrin-1 and netrin-1 pre-conditioned endothelial progenitor cells (EPCs) in vascular protection, specifically related to their anti-restenosis and anti- atherosclerosis effects. Four entirely novel hypotheses will be addressed: 1) Netrin-1 pre-conditioning protects EPCs from oxidative stress induced apoptosis through PI3K-dependent p70s6 kinase activation and Bim inhibition; In addition, mechanistic pathways mediating novel regulatory miRNAs-dependent enhancement of EPC survival by netrin-1 will be fully delineated. By targeting these novel mechanisms, EPC functions can be augmented to attenuate restenosis and atherosclerosis, leading to development of novel therapeutics. 2) Netrin-1 inhibits monocyte activation in a UNC5B (repellant class of netrin-1 receptor)-dependent fashion; and that UNC5B is innovatively regulated by a p47phox-dependent mechanism. Therefore, inhibition of p47phox may potentiate the beneficial effects of netrin-1 in limiting restenosis and atherosclerosis via attenuation of UBC5B expression and UNC5B-dependent monocyte activation. Netrin-1 also inhibits VSMC migration and proliferation via a NO/cGMP/PKG/p38MAPK-dependent mechanism. 3) Administration with netrin-1 or netrin-1 preconditioned EPCs attenuates atherosclerosis in high-fat fed apoE null and LDLR deficient mice. These protective effects are at least in part attributed to augmented EPC function and abrogated monocyte activation, as well as attenuated VSMC proliferation and migration. 4) Endogenous netrin-1 signaling is physiologically protective against restenosis and atherosclerosis, loss of which exaggerates vascular pathologies. We hypothesize that femoral artery injury/high-fat feeding into the netrin-1 or netrin-1/apoE double knockout mice will result in exaggerated restenosis/atherosclerosis. The overall hypothesis is that administration of netrin-1 and netrin-1 preconditioned EPCs remarkably attenuate restenosis and atherosclerosis via mechanisms of augmented EPC function (increased survival, proliferation and homing) to lead to rapid re-endothelialization, attenuated monocyte and VSMC activation, as well as diminished dyslipidemia. Endogenous netrin-1 signaling is physiologically vascular protective, amplification of which with exogenous administration of netrin-1 is necessary to result in sufficient protection, whereas deficiency in the endogenous signaling of netrin-1 (i.e. due to genetic defects) is prone to deteriorated vascular pathologies. Four specific aims are designed to fully address these hypotheses, and accomplishments of the aims may establish netrin-1, netrin-1 pre-conditioned EPCs, and modulators of related pathways as novel therapeutic options for vascular pathologies of restenosis and atherosclerosis.

抽象的 该应用旨在确定Netrin-1和Netrin-1的潜在作用和分子机制 血管保护中的内皮祖细胞（EPC），特别与它们的抗新病和抗 - 动脉粥样硬化作用。将解决四个完全新颖的假设：1）Netrin-1预先调节保护保护 来自氧化应激的EPC通过PI3K依赖性P70S6激酶激活和BIM抑制引起的凋亡。 另外，介导新的调节性miRNA依赖性EPC存活的机械途径通过 Netrin-1将被充分划定。通过针对这些新型机制，可以将EPC函数增强为 减弱再狭窄和动脉粥样硬化，导致新型治疗剂的发展。 2）Netrin-1抑制 UNC5B（Netrin-1受体的驱虫类）依赖性时尚中的单核细胞激活；那Unc5b是 由P47Phox依赖性机制进行创新调节。因此，抑制p47phox可能会增强 Netrin-1通过衰减UBC5B表达和 UNC5B依赖性单核细胞激活。 Netrin-1还通过A抑制VSMC迁移和增殖 否/CGMP/PKG/P38MAPK依赖机制。 3）使用Netrin-1或Netrin-1预处理EPC给药 高脂喂养的ApoE Null和LDLR缺乏小鼠的动脉粥样硬化减弱。这些保护作用至少在 归因于EPC功能增强和废除单核细胞激活以及减弱VSMC的部分 扩散和迁移。 4）内源性Netrin-1信号传导在生理上具有针对再狭窄和 动脉粥样硬化的损失夸大了血管病理。我们假设股动脉损伤/高脂 进食Netrin-1或Netrin-1/ApoE双基因敲除小鼠将导致夸张的再狭窄/动脉粥样硬化。 总体假设是，Netrin-1和Netrin-1预处理EPC的给药显着减弱 通过增强EPC功能的机制再狭窄和动脉粥样硬化（生存率增加，增殖和 归巢）导​​致快速重新皮层化，单核细胞和VSMC激活，并减少 血脂血症。内源性Netrin-1信号传导是生理血管保护性的 Netrin-1的外源给药是为了获得足够的保护而需要的，而缺乏 Netrin-1的内源信号传导（即由于遗传缺陷引起的）容易发生血管病理。四个 具体目的旨在充分解决这些假设，目标的成就可以建立 Netrin-1，Netrin-1预先调节的EPC和相关途径的调节剂，作为新型治疗选择 再狭窄和动脉粥样硬化的血管病理。