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: 8004774
• 负责人: CHIARA GERHARDINGER
• 金额: $ 18.19万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8004774
• 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; abstracting; 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; receptor; research study; retina blood vessel structure; small molecule; sorbinil

Abstract 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.

摘要 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， 控制，我们预计，除了药物，是有效的预排空组织的影响， 残留的高血糖症和长期给药的安全性将使预防成为现实。没有 临床上可用的辅助药物，并且没有关于药物类型的严格的正面或负面信息 其可有效预防人类糖尿病性视网膜病变。因此，我们试图从药物中学习， 预防实验性糖尿病视网膜病变，其中分子过程必须在视网膜血管中沉默， 以预防糖尿病引起的视力损害。我们测试了两种药物， 作用机制（低、中浓度的醛糖还原酶抑制剂和阿司匹林）推理 这两种药物共同的分子靶点将确定候选的致病途径， 进一步调查。实验表明，在大鼠中，（i）糖尿病改变了多个 视网膜血管中的基因，（ii）TGF-β通路是主要受糖尿病影响的单一功能通路， 和（iii）这两种药物有私人和共同的目标，TGF-β途径是其中之一。 共同的功能目标。鉴于TGF-β通路的过度活跃可以解释大部分的血管病变， 糖尿病视网膜病变的组织病理学，并基于额外的结果证明增加TGF-β信号传导 在糖尿病视网膜血管中，我们计划测试过量的TGF-²信号传导有助于糖尿病视网膜血管的假说。 糖尿病视网膜病变的特征性血管病理学。该项目特别令人兴奋的是， 有机会使用一种新的小分子TGF-β I型受体激酶抑制剂，命名为SM 16， 主动，这是平移步骤最吸引人的功能。我们的目标是在糖尿病大鼠中开发和验证一种药物， 基于SM16的策略，用于非侵入性，长期和靶向预防过度TGF-β信号传导， 视网膜血管确切的目的是使TGF-β信号恢复到对照值，而不降低基础TGF-β。 活动。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病变的分子影响。 船舶.然后，我们将测试是否通过消除这些影响，视网膜毛细血管受到保护， 细胞死亡和重塑导致它们在糖尿病中最终死亡。在相同的大鼠中，我们还将检查 SM16对典型肾脏病理学发展的影响。最后，我们将研究TGF-β 人糖尿病视网膜血管（死后眼睛）中的通路。一个积极的结果相结合， 临床前研究和人类糖尿病视网膜将确定过量的TGF-β信号作为一个贡献者， 糖尿病视网膜病变的血管病理学，并将刺激药物的研究和开发， 安全地调节人类TGF-β活性。此外，这些研究还准备为 抗TGF-β治疗在其他疾病中的应用。