Mechanisms regulating VEGF receptors in diabetic angiogenesis

糖尿病血管生成中 VEGF 受体的调节机制

• 批准号: 10666497
• 负责人: Hong Chen
• 金额: $ 81.45万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666497
• 关键词: Acceleration; Adaptor Signaling Protein; Affect; Amputation; Angiogenesis Inhibitors; Animal Model; Animals; Arteries; Atherosclerosis; Autophagocytosis; Autophagosome; Binding; Biological Models; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Cell Separation; Cell physiology; Chronic; Complications of Diabetes Mellitus; Data; Degradation Pathway; Deposition; Development; Diabetes Mellitus; Diabetic mouse; Disease; Endothelial Cells; Endothelial Growth Factors Receptor; Endothelium; Epigenetic Process; Family; Funding; Gene Expression; Genetic; Goals; Growth; Growth Factor Receptors; Hyperglycemia; Impairment; In Vitro; Infection; Insulin Resistance; Intention; KDR gene; Leg; Life; Limb structure; Lower Extremity; Lymphangiogenesis; Maps; Mediating; Medical; Medical Care Costs; Mission; Molecular; Molecular Target; Mus; Mutant Strains Mice; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Peripheral arterial disease; Persons; Phosphotransferases; Play; Post-Translational Regulation; Process; Productivity; Proteins; Retinal Diseases; Role; Signal Transduction; Streptozocin; Stroke; Testing; Therapeutic; Tube; Ubiquitination; Ulcer; United States; United States National Institutes of Health; Untranslated RNA; Up-Regulation; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascularization; angiogenesis; cell motility; cost; db/db mouse; diabetic; diabetic patient; diabetic ulcer; epsin; epsin 1; experimental study; forkhead protein; in vitro Model; in vivo; in vivo evaluation; limb amputation; migration; mouse model; neovascularization; new growth; novel; novel strategies; novel therapeutic intervention; novel therapeutics; prevent; receptor; response; skin ulcer; targeted treatment; transcription factor; transcriptome sequencing; ubiquitin-protein ligase; wound healing

PROJECT SUMMARY/ABSTRACT Diabetes affects over 30 million people in the United States and costs a staggering $327 billion a year in direct medical costs and lost productivity. Diabetes adversely affects blood vessels as hyperglycemia and insulin resistance are key players in the development of atherosclerosis, peripheral neuropathy, retinopathy, and peripheral artery disease. Peripheral artery disease is a chronic condition where fatty deposits called plaques build up in the arteries to the legs, resulting in ulcerations and infections, which precedes 85% of diabetes- related amputations. Our goal is to understand how chronic hyperglycemia impairs vascular endothelial cell function to identify molecular targets that will form the basis for new therapeutic approaches to treat ulcerations and the other vascular complications of diabetes. Vascular endothelial growth factor receptors 2 and 3 (VEGFR2/3) are critical regulators of blood vessel growth or angiogenesis. These receptors are significantly reduced in the vascular endothelium of diabetic patients, resulting in inadequate angiogenesis. In our previously funded application, we showed that diabetic conditions induced expression of autophagosome proteins and promoted degradation of VEGFR2/3. In particular, we identified the protein Unc-51-like autophagy activating kinase 1 (Ulk1) as an important inhibitor of angiogenesis by stimulating autophagosome formation causing selective degradation of VEGFR2/3. Loss of endothelial Ulk1 elevated VEGFR2/3 levels and enhanced angiogenic responses such as endothelial cell proliferation, migration, and tube formation. In this competing renewal application, we present compelling preliminary data demonstrating the Forkhead box O1 transcription factor (FoxO1) controls expression of endothelial Ulk1 in both in vivo and in vitro diabetic model systems and that deficiency of endothelial FoxO1 inhibits autophagosome formation. We also show the noncoding RNA miR183-3p inhibits endothelial FoxO1 expression and the deficiency of epsin 1 and 2 adaptor proteins promotes FoxO1 ubiquitination and degradation in diabetes. These findings strongly suggest that targeting FoxO1 to protect VEGFR2/3 from degradation may represent a novel therapeutic strategy to prevent inadequate vascularization in diabetic ulcers. In view of that, we will investigate the following Specific Aims using unique mutant mice as well as in vitro models of diabetes: 1) determine the molecular mechanisms underlying FoxO1-mediated inhibition of neovascularization in diabetes, 2) determine the molecular mechanisms regulating FoxO1 activity in the diabetic endothelium, and 3) determine the therapeutic potential of targeting FoxO1 by genetic deletion or miR183-3p-mediated inhibition in diabetic angiogenesis. Our findings will enhance understanding of the cellular mechanisms behind VEGFR2/3 loss and activation of FoxO1 in regulating blood vessel damage in diabetes. We anticipate that therapies targeting FoxO1 may be useful for restoring peripheral angiogenesis to ameliorate the vascular complications associated with diabetes.

项目总结/摘要 糖尿病影响着美国3000多万人，每年直接花费惊人的3270亿美元。 医疗成本和生产力损失。糖尿病对血管有不良影响，如高血糖和胰岛素 耐药性是动脉粥样硬化、周围神经病变、视网膜病变和 外周动脉疾病外周动脉疾病是一种慢性疾病， 在腿部的动脉中积聚，导致溃疡和感染，这是85%的糖尿病的先兆- 相关的截肢我们的目标是了解慢性高血糖如何损害血管内皮细胞 功能，以确定分子靶点，将形成新的治疗方法，以治疗溃疡的基础 和其他糖尿病血管并发症。血管内皮生长因子受体2和3 血管内皮生长因子受体2/3（VEGFR 2/3）是血管生长或血管生成的关键调节因子。这些受体明显 糖尿病患者的血管内皮细胞减少，导致血管生成不足。在我们 先前资助的申请，我们发现糖尿病条件诱导自噬体的表达， 蛋白质，并促进VEGFR 2/3的降解。特别是，我们鉴定了Unc-51样自噬蛋白， 激活激酶1（Ulk 1）通过刺激自噬体形成作为血管生成的重要抑制剂 导致VEGFR 2/3的选择性降解。内皮细胞Ulk 1的缺失升高了VEGFR 2/3水平， 增强的血管生成反应，如内皮细胞增殖、迁移和管形成。在这 竞争的更新应用程序，我们提出了令人信服的初步数据表明，叉头盒O 1 转录因子FoxO 1在体内和体外糖尿病模型中调控内皮细胞Ulk 1的表达 系统和内皮FoxO 1的缺陷抑制自噬体的形成。我们还展示了 非编码RNA miR 183 - 3 p抑制内皮细胞FoxO 1表达和epsin 1和2衔接子缺陷 蛋白质促进FoxO 1泛素化和降解糖尿病。这些发现有力地表明， 靶向FoxO 1以保护VEGFR 2/3免于降解可能代表了一种新的治疗策略， 糖尿病性溃疡血管形成不足。有鉴于此，我们将研究以下具体目标 使用独特的突变小鼠以及糖尿病的体外模型：1）确定分子机制 潜在的FoxO 1介导的糖尿病新生血管抑制，2）确定分子 调节糖尿病内皮细胞FoxO 1活性的机制，以及3）确定治疗潜力 通过基因缺失或miR 183 - 3 p介导的抑制FoxO 1在糖尿病血管生成中的作用。我们的研究结果 将增强对VEGFR 2/3丢失和FoxO 1激活背后的细胞机制的理解， 调节糖尿病中的血管损伤。我们预计，靶向FoxO 1的治疗可能有助于 恢复外周血管生成以改善与糖尿病相关的血管并发症。

项目成果

Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development.

• DOI: 10.1172/jci129374
• 发表时间: 2020-09
• 期刊: The Journal of clinical investigation
• 作者: Kai Song;Xiaofeng S Cai;Yunzhou Dong;Hao Wu;Yong Wei;U. Shankavaram;Kui Cui;Yang Lee;Bo Zhu;Sudarshan Bhattacharjee;Beibei Wang;Kun Zhang;Aiyun Wen;Scott W. Wong;Lili Yu;Lijun Xia;A. Welm;D. Bielenberg;K. Camphausen;Yibin Kang;Hong Chen

Role of endoplasmic reticulum stress signalling in diabetic endothelial dysfunction and atherosclerosis.

• DOI: 10.1177/1479164116666762
• 发表时间: 2017-01
• 期刊: Diabetes & vascular disease research
• 影响因子: 2.4
• 作者: Dong Y;Fernandes C;Liu Y;Wu Y;Wu H;Brophy ML;Deng L;Song K;Wen A;Wong S;Yan D;Towner R;Chen H
• 通讯作者: Chen H

Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function.

• DOI: 10.1126/scisignal.2005413
• 发表时间: 2014-10-14
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Liu X;Pasula S;Song H;Tessneer KL;Dong Y;Hahn S;Yago T;Brophy ML;Chang B;Cai X;Wu H;McManus J;Ichise H;Georgescu C;Wren JD;Griffin C;Xia L;Srinivasan RS;Chen H
• 通讯作者: Chen H

Vascular Injury in the Zebrafish Tail Modulates Blood Flow and Peak Wall Shear Stress to Restore Embryonic Circular Network.

斑马鱼尾的血管损伤调节血流和峰值壁剪应力以恢复胚胎圆网。

• DOI: 10.3389/fcvm.2022.841101
• 发表时间: 2022
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Baek KI;Chang SS;Chang CC;Roustaei M;Ding Y;Wang Y;Chen J;O'Donnell R;Chen H;Ashby JW;Xu X;Mack JJ;Cavallero S;Roper M;Hsiai TK
• 通讯作者: Hsiai TK

Mimetic peptide of ubiquitin-interacting motif of epsin as a cancer therapeutic-perspective in brain tumor therapy through regulating VEGFR2 signaling.

• DOI: 10.20517/2574-1209.2016.01
• 发表时间: 2017
• 期刊: Vessel plus
• 作者: Dong Y;Wu H;Dong J;Song K;Rahman HA;Towner R;Chen H
• 通讯作者: Chen H