CaMKII as a regulator of diabetic retinopathy

CaMKII 作为糖尿病视网膜病变的调节因子

• 批准号: 8820648
• 负责人: Isabella Maria Grumbach
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820648
• 关键词: Accounting; Adult; Apoptosis; Background Diabetic Retinopathy; Basement membrane; Blindness; Blood Vessels; Blood capillaries; Calmodulin; Caring; Characteristics; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Diagnosis; Disease; Disease Progression; Early Diagnosis; Early treatment; Endothelial Cells; Endothelium; Extravasation; Functional disorder; Glucose; Goals; Health Care Costs; Healthcare; Healthcare Systems; Human; Hyperglycemia; Imaging Techniques; In Vitro; Injury; Insulin-Dependent Diabetes Mellitus; Knowledge; Mediating; Medical; Mission; Mitochondria; Molecular; Molecular Target; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Permeability; Phenotype; Phosphotransferases; Play; Production; Publishing; Reactive Oxygen Species; Reporting; Research; Retinal; Retinal Diseases; Role; Signal Transduction; Staging; Steroids; Stress; Structure; System; Testing; Transgenic Mice; Validation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Endothelium; Veterans; Work; aged; angiogenesis; base; burden of illness; capillary; design; endothelial dysfunction; experience; in vivo; in vivo Model; inhibitor/antagonist; innovation; interest; laser photocoagulation; meetings; mitochondrial dysfunction; mouse model; novel; novel strategies; novel therapeutics; overexpression; oxidation; prevent; public health relevance; research study; standard care; tool; treatment strategy

DESCRIPTION (provided by applicant): Almost 25% of the veterans that are currently receiving healthcare through the VA system carry the diagnosis of diabetes. Nearly all veterans with type 1 diabetes and >60% of veterans with type 2 develop retinopathy during the first two decades of disease, 1% will experience severe visual loss or blindness. Current therapies provide clinically meaningful improvement in only 50% of veterans. Thus, there is a critical need to identify regulators of DR, which can be targeted therapeutically and will directly benefit a large group of veterans. We hypothesize that the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) under hyperglycemic conditions promotes the endothelial pathology characteristic for diabetic retinopathy (DR), in particular endothelial apoptosis and barrier dysfunction. Thus, CaMKII inhibition may be a potent novel approach to prevent or treat DR. The long-term goal of the Grumbach lab is to study the function of CaMKII in the vasculature, specifically CaMKII modulation as a new approach to treat vascular disease. The objective of this project is to determine whether specific CaMKII inhibition in endothelium prevents non-proliferative DR. The central hypothesis is that CaMKII inhibition decreases non-proliferative DR by preventing endothelial apoptosis and barrier dysfunction, two key phenotypes of non-proliferative DR. We will test the hypothesis in a novel in vivo mouse model in which the potent and specific endogenous CaMKII inhibitor CaMKIIN is selectively overexpressed in endothelium and dissect molecular mechanisms in vitro. The rationale for the proposed studies is that, understanding whether CaMKII regulates the phenotypic changes of non- proliferative DR in vivo and drives endothelial cells ROS-production, apoptosis and barrier function may be a critical first step towards designing a specific CaMKII inhibitor to prevent and alleviate DR. We will test our central hypothesis in two specific aims: 1) Determine the role of endothelial CaMKII on non-proliferative DR in vivo, 2): Characterize whether CaMKII controls endothelial dysfunction under high glucose conditions in vitro. In the first aim, the novel in vivo model will be used to test whether CaMKII inhibition wil preserve retinal microvascular structure and function in non-proliferative DR. Under aim 2, we will define the mechanisms through which CaMKII is activated under hyperglycemia and regulates barrier function, apoptosis and ROS production in vitro. The approach is innovative because of its use of novel in vivo models and imaging techniques and specific tools to dissect CaMKII signaling. The proposed research is significant because it is expected to advance the field by defining CaMKII as a novel molecular target that controls endothelial phenotypes in DR. Ultimately, such knowledge may allow for the development of new therapeutic strategies in DR that will benefits our veterans.

描述（由申请人提供）： 目前通过 VA 系统接受医疗保健的退伍军人中，近 25% 被诊断患有糖尿病。几乎所有患有 1 型糖尿病的退伍军人和 > 60% 患有 2 型糖尿病的退伍军人在患病的前 20 年都会出现视网膜病变，其中 1% 的人会出现严重的视力丧失或失明。目前的疗法仅对 50% 的退伍军人提供了具有临床意义的改善。因此，迫切需要确定 DR 的调节因子，这些调节因子可以作为治疗目标，并直接使一大批退伍军人受益。我们假设高血糖条件下多功能 Ca2+/钙调蛋白依赖性激酶 II (CaMKII) 会促进糖尿病视网膜病变 (DR) 的内皮病理特征，特别是内皮细胞凋亡和屏障功能障碍。因此，CaMKII 抑制可能是预防或治疗 DR 的有效新方法。 Grumbach 实验室的长期目标是研究 CaMKII 在脉管系统中的功能，特别是 CaMKII 调节作为治疗血管疾病的新方法。该项目的目的是确定内皮细胞中的特异性 CaMKII 抑制是否可以预防非增殖性 DR。中心假设是 CaMKII 抑制通过防止内皮细胞凋亡和屏障功能障碍（非增殖性 DR 的两个关键表型）来减少非增殖性 DR。我们将在一种新型体内小鼠模型中检验这一假设，其中有效且特异性的内源性 CaMKII 抑制剂 CaMKIIN 在内皮细胞中选择性过表达，并在体外剖析分子机制。拟议研究的基本原理是，了解 CaMKII 是否在体内调节非增殖性 DR 的表型变化并驱动内皮细胞 ROS 产生、凋亡和屏障功能，可能是设计特异性 CaMKII 抑制剂以预防和治疗的关键第一步。缓解DR。我们将在两个具体目标中测试我们的中心假设：1）确定内皮 CaMKII 在体内非增殖性 DR 中的作用，2）：表征 CaMKII 是否在体外高葡萄糖条件下控制内皮功能障碍。第一个目标是，新的体内模型将用于测试 CaMKII 抑制是否会保留非增殖性 DR 中的视网膜微血管结构和功能。在目标 2 下，我们将定义 CaMKII 在高血糖下被激活并在体外调节屏障功能、细胞凋亡和 ROS 产生的机制。该方法具有创新性，因为它使用了新颖的体内模型和成像技术以及特定工具来剖析 CaMKII 信号传导。这项研究意义重大，因为它有望通过将 CaMKII 定义为控制 DR 内皮表型的新型分子靶点来推进该领域的发展。最终，这些知识可能有助于开发新的 DR 治疗策略，这将使我们的退伍军人受益。