Mechanisms of action of drugs that prevent experimental diabetic retinopathy

预防实验性糖尿病视网膜病变药物的作用机制

• 批准号: 7582470
• 负责人: CHIARA GERHARDINGER
• 金额: $ 48.13万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7582470
• 关键词: Address; Affect; Age; Aldehyde Reductase; Animals; Apoptosis; Apoptotic; Aspirin; Atherosclerosis; Attenuated; Autopsy; Back; Blood Vessels; Blood capillaries; Candidate Disease Gene; Cause of Death; Cell Cycle; Cell Death; Cessation of life; Characteristics; Clinical; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic Retinopathy; Drug Delivery Systems; Drug effect disorder; Elements; Endothelial Cells; Experimental Diabetes Mellitus; Extracellular Matrix; Eye; Family; Gender; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Growth Factor; Histopathology; Human; Hyperglycemia; Hypertension; Individual; Inflammation; Investigation; Kidney; Kidney Diseases; Lead; Learning; Measures; Medicine; Messenger RNA; Molecular; Molecular Target; Names; Oral cavity; Oxidative Stress; Pathology; Pathway interactions; Pericytes; Pharmaceutical Preparations; Phosphotransferases; Prevention; Prevention strategy; Process; Proteins; Rattus; Residual state; Retina; Retinal; Retinal Diseases; Role; Signal Transduction; Staging; Streptozocin; Syndrome; Testing; Tissues; Vision; Work; base; capillary; clinical application; connective tissue growth factor; diabetic; diabetic rat; drug development; efficacy testing; glycemic control; inhibitor/antagonist; interest; malformation; member; non-diabetic; novel; preclinical study; prevent; public health relevance; receptor; research study; retina blood vessel structure; small molecule; sorbinil

DESCRIPTION (provided by applicant): The ultimate goal of our work is to develop drug strategies for the prevention of diabetic retinopathy. Prevention has been brought within reach by the progressively wider implementation of intensive glycemic control, and we anticipate that the addition of drugs that are effective in pre-emptying the tissue effects of residual hyperglycemia and are safe for long-term administration will make prevention a reality. There are no adjunct drugs usable clinically, and there are no rigorous positive or negative information on the type of drugs that may be effective in the prevention of human diabetic retinopathy. We thus sought to learn from drugs that prevent experimental diabetic retinopathy which molecular processes must be silenced in the retinal vessels in order to prevent the sight-threatening damage induced by diabetes. We tested two drugs with different mechanisms of action (an aldose reductase inhibitor and aspirin at low-intermediate concentrations) reasoning that molecular targets common to the two drugs would identify candidate pathogenic pathways to be investigated further. The experiments showed that, in rats, (i) diabetes changes the expression of multiple genes in retinal vessels, (ii) the TGF-¿ pathway was the single functional pathway mostly affected by diabetes, and (iii) the two drugs had private as well as common targets, with the TGF- ¿ pathway being one of the two common functional targets. Given that overactivity of the TGF- ¿ pathway could explain much of the vascular histopathology of diabetic retinopathy, and based on additional results documenting increased TGF- ¿ signaling in diabetic retinal vessels, we plan to test the hypothesis that excess TGF- ¿ signaling contributes to the characteristic vascular pathology of diabetic retinopathy. The project is made especially exciting by the opportunity to use a new small molecule inhibitor of TGF- ¿ type I receptor kinase, named SM16, that is orally active, a most appealing feature for translational steps. We aim to develop and validate in diabetic rats a drug strategy based on SM16 for non-invasive, long-term, and on-target prevention of the excess TGF- ¿ signaling in retinal vessels. The precise aim is to bring TGF- ¿ signaling back to control values without reducing basal TGF- ¿ activity. We will use the inhibitor to learn the molecular effects of excess TGF- ¿ signaling on diabetic retinal vessels. We will then test whether by taking away such effects, the retinal capillaries are protected from the cell death and remodeling that lead to their final demise in diabetes. In the same rats we will also examine the effects of SM16 on the development of the typical renal pathology. Finally, we will examine the TGF- ¿ pathway in human diabetic retinal vessels (postmortem eyes). A combination of positive results in the preclinical studies and the human diabetic retina will identify excess TGF- ¿ signaling as a contributor to the vascular pathology of diabetic retinopathy and will stimulate investigation and development of drugs to modulate safely TGF- ¿ activity in humans. In addition, the studies are poised to generate a paradigm for applications of anti-TGF- ¿ therapy to other pathologies. PUBLIC HEALTH RELEVANCE: The studies proposed address diabetic retinopathy, the most common and dreaded complication of diabetes. We seek to identify processes that are active at early stages of the development of retinopathy, so that we may develop the best drug strategy for prevention of the damage inflicted by diabetes to the retinal vessels. Such work has now uncovered a possible role in diabetic retinopathy of a multifunctional growth factor named TGF- ¿. TGF- ¿ has been known to be involved in several vascular pathologies, but has never before been associated with diabetic retinopathy. This project intends to test whether reducing the increased TGF- ¿ caused by diabetes will protect the retinal vessels from damage and ultimately death. The project is exciting for three reasons. First, it will test a new inhibitor of TGF- ¿ that can be administered by mouth, and therefore would accelerate potential clinical application. Second, if the results show that returning to normal levels the excess TGF- ¿ activity caused by diabetes does in fact protect the retinal vessels, we will have a precise molecular target to be brought to test for the prevention of human diabetic retinopathy. Third, being TGF- ¿ implicated in multiple vascular pathologies - from kidney disease in diabetic and nondiabetic individuals, to vascular malformations in genetic syndromes, to abnormal vascular wall remodeling in hypertension and atherosclerosis -, the development of drug strategies to modulate the activity of TGF- ¿ will find interest and use in several fields of medicine.

描述（由申请人提供）：我们工作的最终目标是开发预防糖尿病视网膜病变的药物策略。通过逐步广泛实施强化血糖控制，预防已触手可及，我们预计，添加有效预排空残留高血糖组织效应且长期给药安全的药物将使预防成为现实。没有临床上可用的辅助药物，也没有严格的积极或消极的信息类型的药物，可能是有效的预防人类糖尿病视网膜病变。因此，我们试图从预防实验性糖尿病视网膜病变的药物中了解到，为了防止糖尿病引起的威胁视力的损害，视网膜血管中的分子过程必须沉默。我们测试了两种具有不同作用机制的药物（低-中等浓度的醛糖还原酶抑制剂和阿司匹林），理由是这两种药物共同的分子靶点将确定待进一步研究的候选致病途径。实验表明，在大鼠中，（i）糖尿病改变了视网膜血管中多个基因的表达，（ii）TGF-β通路是主要受糖尿病影响的单一功能通路，（iii）这两种药物有私人和共同的靶点，TGF-β通路是两个共同的功能靶点之一。鉴于TGF-β通路的过度活跃可以解释糖尿病视网膜病变的大部分血管组织病理学，并且基于记录糖尿病视网膜血管中TGF-β信号增加的额外结果，我们计划测试过度TGF-β信号有助于糖尿病视网膜病变的特征性血管病理学的假设。该项目特别令人兴奋的是有机会使用一种新的TGF-β I型受体激酶的小分子抑制剂，名为SM16，它是口服活性的，这是翻译步骤最吸引人的特征。我们的目标是在糖尿病大鼠中开发和验证一种基于SM16的药物策略，用于非侵入性，长期和靶向预防视网膜血管中过量的TGF-β信号传导。确切的目标是使TGF-β信号回到控制值，而不降低基础TGF-β活性。我们将使用这种抑制剂来了解过量TGF-β信号对糖尿病视网膜血管的分子效应。然后，我们将测试是否通过消除这些影响，视网膜毛细血管被保护免受细胞死亡和重塑，导致他们在糖尿病中的最终死亡。在相同的大鼠中，我们还将检查SM 16对典型肾脏病理学发展的影响。最后，我们将研究人类糖尿病视网膜血管（死后眼睛）中的TGF-β通路。临床前研究和人类糖尿病视网膜中的阳性结果的组合将确定过量的TGF-β信号传导作为糖尿病视网膜病变的血管病理学的贡献者，并将刺激药物的研究和开发，以安全地调节人类的TGF-β活性。此外，这些研究有望为抗TGF-β治疗在其他疾病中的应用提供一个范例。公共卫生相关性：这些研究旨在解决糖尿病视网膜病变，糖尿病最常见和最可怕的并发症。我们试图确定在视网膜病变发展的早期阶段活跃的过程，以便我们可以开发预防糖尿病对视网膜血管造成损害的最佳药物策略。这项工作现在已经发现了一种名为TGF-β的多功能生长因子在糖尿病视网膜病变中的可能作用。已知TGF-β参与多种血管病变，但以前从未与糖尿病视网膜病变相关。该项目旨在测试减少糖尿病引起的TGF-β增加是否会保护视网膜血管免受损伤并最终死亡。这个项目之所以令人兴奋，有三个原因。首先，它将测试一种新的TGF-β抑制剂，可以通过口服给药，因此将加速潜在的临床应用。其次，如果结果表明，恢复正常水平的过度TGF-β活性引起的糖尿病实际上保护视网膜血管，我们将有一个精确的分子靶点来测试预防人类糖尿病视网膜病变。第三，作为TGF-β由于TGF-β与多种血管病理学有关--从糖尿病和非糖尿病个体的肾脏疾病到遗传综合征中的血管畸形，再到高血压和动脉粥样硬化中的异常血管壁重塑--因此，开发调节TGF-β活性的药物策略将在多个医学领域引起兴趣和使用。