BMP2/ALKs signaling system in diabetic retinopathy

BMP2/ALKs信号系统在糖尿病视网膜病变中的作用

• 批准号: 9886394
• 负责人: Mohamed Al-Sayed Al-Shabrawey
• 金额: $ 38.34万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886394
• 关键词: Activin Receptor; Activins; Address; Adult; Affect; Affinity; Age; Attenuated; Autoimmunity; BMP4; BMPR2 gene; Basement membrane; Binding; Blindness; Blood Preservation; Blood capillaries; Blood-Retinal Barrier; Clinical; Complications of Diabetes Mellitus; Data; Deposition; Development; Diabetes Mellitus; Diabetic Retinopathy; Diabetic mouse; Endothelial Cells; Endothelium; Enrollment; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fibronectins; Functional disorder; Genes; Genome; Glucose; Goals; Human; Inflammatory; Knockout Mice; Knowledge; Lead; Link; MAP Kinase Gene; Mediating; Mission; Modality; Molecular; Monitor; Mus; National Eye Institute; Outcome; Pathogenesis; Pathway interactions; Permeability; Pharmacology; Phosphotransferases; Play; Prevention; Retina; Role; Sampling; Serum; Signal Transduction; Streptozocin; System; Testing; Therapeutic; Transforming Growth Factors; United States National Institutes of Health; Up-Regulation; Vascular Endothelial Growth Factors; Visual; attenuation; blood glucose regulation; bone morphogenetic protein 2; bone morphogenetic protein receptor type I; bone morphogenetic protein receptors; cohort; conditional knockout; connective tissue growth factor; cytokine; diabetic; diabetic patient; endothelial dysfunction; genetic manipulation; human subject; improved; inhibitor/antagonist; intravitreal injection; laser photocoagulation; macular edema; mouse model; new therapeutic target; p38 Mitogen Activated Protein Kinase; phenome; prevent; prospective; receptor; recruit; retina blood vessel structure; retinal damage; side effect; therapeutic target

Summary Breakdown of the blood-retinal barrier (BRB) and thickening of the endothelial cell basement membrane due to deposition of extracellular matrix (ECM) are early events in the pathogenesis of diabetic retinopathy (DR). Current treatments are limited by significant side effects, including ECM deposition. Bone morphogenetic protein- 2 (BMP2), a secreted cytokine belonging to the TGF-β superfamily initiates signaling through activin receptors like kinases (Alk1, 2, 3, and 6) with high affinity to Alk2 and 3. The goal of this project is to test the hypothesis that in diabetes, BMP2 compromises BRB and induces ECM formation through the endothelial Alk2/3-dependent mechanism. Our hypothesis is supported by compelling preliminary findings that retinal and circulating BMP2 are upregulated in diabetic humans and mice, as well as in human retinal endothelial cells (HRECs) subjected to high glucose (HG). Importantly, BMP2 inhibitors attenuate the permeability and ECM deposition effect of HG in HRECs. Moreover, BMP2 activates the canonical and non-canonical pathways (smad/Runx2 and p38 MAPK/NFB, respectively) in HRECs. Our hypothesis predicts that in diabetes BMP2 activates smad and p38 MAPK pathways integrate at wnt/-catenin to induce hyperpermeability and ECM deposition. We will test the following specific aims: 1. Activated BMP2/Alks signaling system contributes to retinal endothelial cell dysfunction in DR: We will correlate changes in circulating levels of BMPs to the development of DR using serum samples from a large cohort of diabetic patients enrolled in the Phenome and Genome of Diabetes Autoimmunity (PAGODA) study and have been prospectively monitored for the development of diabetic complications including DR in the last 15 years. Using a streptozotocin-induced diabetic mouse model, and HRECs subjected to HG, we will determine the levels and distribution of BMP2 signaling system (BMP2, BMP4, BMP receptors, smad1/5/9, Runx2, and negative regulators of BMP2 such as noggin and BMP-binding endothelial regulator (BMPER). Subsequently, we will study the effects of pharmacological inhibition or genetic manipulation of the BMP2/Alks system on BRB function, and ECM. We will use endothelial Alk2/3 conditional knockout mice developed within our lab and commercially available BMPER-deficient mice (BMPER+/−) and; 2. Both canonical and non-canonical pathways contribute to BMP2-mediated retinal endothelial cell dysfunction in DR: We will test a) the effect of modulation of BMP2/Alks signaling on the smad1/5/9 and p38/NFB pathways under normal or diabetic conditions, b) the effect of inhibition of smad1/5/9 or p38/NFB signaling on diabetes or BMP2-induced permeability and ECM deposition, and c) the role of the wnt/catenin pathway as a potential downstream target from both p38/NFB and smad1/5/9 pathways to mediate retinal microvascular damage induced by BMP2. The translational significance of this proposal is the therapeutic potential of inhibition of BMP2/Alks signaling to improve the visual outcomes in DR with the ultimate goal of overcoming the limiting factors of current therapies in the prevention of ECM deposition.

概括 血液 - 视网膜屏障（BRB）的崩溃和内皮细胞基底膜的增厚 细胞外基质（ECM）的沉积是糖尿病性视网膜病（DR）发病机理的早期事件。 当前治疗受到重大副作用的限制，包括ECM沉积。骨形态发生蛋白 2（BMP2），属于TGF-β超家族的分泌细胞因子通过激活素受体启动信号传导 像激酶（ALK1、2、3和6）对ALK2和3的亲和力高。该项目的目的是检验假设 在糖尿病中，BMP2损害了BRB并通过内皮ALK2/3依赖性诱导ECM形成 机制。我们的假设得到了令人信服的初步发现，即视网膜和循环BMP2 在糖尿病人类和小鼠以及受到的人类残留内皮细胞（HREC）中被上调 高葡萄糖（HG）。重要的是，BMP2抑制剂减弱了HG的渗透性和ECM沉积效应 在HREC中。此外，BMP2激活规范和非典型途径（SMAD/RUNX2和P38 MAPK/NFB，分别在HREC中。我们的假设预测糖尿病中BMP2激活SMAD和p38 在Wnt/-catenin集成的MAPK途径诱导过度过敏性和ECM沉积。我们将测试 以下特定目的：1。激活的BMP2/ALKS信号系统有助于永久内皮细胞 DR的功能障碍：我们将将BMP循环水平的变化与DR的开发相关联 来自糖尿病现象和基因组的大量糖尿病患者的血清样品 自身免疫性（PAGODA）研究，并已预先监测糖尿病的发展 并发症，包括过去15年中的DR。使用链蛋白酶诱导的糖尿病小鼠模型，并使用 受HG的HRECS，我们将确定BMP2信号系统的水平和分布（BMP2，BMP4， BMP受体，Smad1/5/9，Runx2和BMP2的负调节剂，例如Noggin和BMP结合内皮 调节器（BMPER）。随后，我们将研究药物抑制或遗传操作的影响 BRB功能和ECM的BMP2/ALKS系统我们将使用内皮ALK2/3条件敲除小鼠 在我们的实验室中开发，并在市售的BMPER缺陷小鼠（BMPER +/-）中开发； 2。两者都有规范 非典型途径有助于BMP2介导的残留内皮细胞功能障碍DR：我们 将测试a）BMP2/ALKS信号在正常下调制对SMAD1/5/9和P38/NFB途径的效果 或糖尿病状况，b）抑制SMAD1/5/9或P38/NFB信号对糖尿病或BMP2诱导的抑制作用 渗透性和ECM沉积，c）wnt/氨酸途径的作用 来自p38/nfb和smad1/5/9途径的靶标介导BMP2引起的常规微血管损伤。 该建议的翻译意义是抑制BMP2/ALKS信号的治疗潜力 以克服当前的限制因素的最终目标，以改善DR的视觉结果 预防ECM沉积的疗法。