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

基本信息

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
项目类别：
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

项目摘要

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.

概括血视网膜屏障（BRB）的破坏和内皮细胞基底膜的增厚细胞外基质（ECM）沉积是糖尿病视网膜病变（DR）发病机制的早期事件。目前的治疗方法受到明显副作用的限制，包括 ECM 沉积。 2 (BMP2)，一种属于 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）与 Alk2 和 3 具有高亲和力。该项目的目标是检验假设在糖尿病中，BMP2 损害 BRB 并通过内皮 Alk2/3 依赖性诱导 ECM 形成我们的假设得到了视网膜和循环 BMP2 令人信服的初步结果的支持。在糖尿病人和小鼠以及人视网膜内皮细胞 (HREC) 中表达上调重要的是，BMP2 抑制剂可减弱 HG 的渗透性和 ECM 沉积作用。此外，BMP2 激活规范和非规范途径（smad/Runx2 和 p38）。我们的假设预测，在糖尿病中，BMP2 会激活 smad 和 p38。 MAPK 通路在 wnt/-连环蛋白处整合以诱导通透性过高和 ECM 沉积。具体目标如下： 1. 激活BMP2/Alks信号系统有助于视网膜内皮细胞 DR 功能障碍：我们将使用 BMP 循环水平的变化与 DR 的发展相关联来自参加糖尿病表型组和基因组研究的大量糖尿病患者的血清样本自身免疫（PAGODA）研究，并已对糖尿病的发展进行前瞻性监测过去 15 年使用链脲佐菌素诱导的糖尿病小鼠模型，包括 DR 等并发症。 HRECs经HG处理后，我们将确定BMP2信号系统（BMP2、BMP4、 BMP 受体、smad1/5/9、Runx2 和 BMP2 的负调节因子，例如 noggin 和 BMP 结合内皮细胞随后，我们将研究药理抑制或基因操纵的影响。 BMP2/Alks 系统对 BRB 功能和 ECM 的影响我们将使用内皮 Alk2/3 条件敲除小鼠。我们实验室开发的和市售的 BMPER 缺陷小鼠 (BMPER+/-) 以及；2. 和非经典途径导致 DR 中 BMP2 介导的视网膜内皮细胞功能障碍：我们将测试a)正常情况下BMP2/Alks信号调节对smad1/5/9和p38/NFB通路的影响或糖尿病状况，b) 抑制 smad1/5/9 或 p38/NFκB 信号传导对糖尿病或 BMP2 诱导的影响渗透性和 ECM 沉积，以及 c) wnt/连环蛋白途径作为潜在下游的作用 p38/NF-B 和 smad1/5/9 通路的靶标介导 BMP2 诱导的视网膜微血管损伤。该提案的转化意义在于抑制 BMP2/Alks 信号传导的治疗潜力改善 DR 的视觉效果，最终目标是克服当前的限制因素预防 ECM 沉积的治疗方法。