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: 8007361
• 负责人: CHIARA GERHARDINGER
• 金额: $ 46.21万
• 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/8007361
• 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; TGF-beta type I receptor; Testing; Tissues; Transforming Growth Factor beta; Vision; Work; base; capillary; clinical application; connective tissue growth factor; diabetic; diabetic rat; drug development; efficacy testing; glycemic control; human TGFB1 protein; inhibitor/antagonist; interest; malformation; member; non-diabetic; novel; preclinical study; prevent; 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-beta 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-beta pathway being one of the two common functional targets. Given that overactivity of the TGF-beta pathway could explain much of the vascular histopathology of diabetic retinopathy, and based on additional results documenting increased TGF-beta signaling in diabetic retinal vessels, we plan to test the hypothesis that excess TGF-beta 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-beta 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-beta signaling in retinal vessels. The precise aim is to bring TGF-beta signaling back to control values without reducing basal TGF-beta activity. We will use the inhibitor to learn the molecular effects of excess TGF-beta 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-beta 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-beta signaling as a contributor to the vascular pathology of diabetic retinopathy and will stimulate investigation and development of drugs to modulate safely TGF-beta activity in humans. In addition, the studies are poised to generate a paradigm for applications of anti-TGF-beta therapy to other pathologies.

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。随着强化血糖控制的逐步广泛实施，预防已经触手可及，我们预计，添加可有效预防残余高血糖对组织影响且长期给药安全的药物将使预防成为现实。临床上尚无可用的辅助药物，也没有关于可能有效预防人类糖尿病视网膜病变的药物类型的严格的正面或负面信息。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哪些分子过程必须在视网膜血管中沉默，以防止糖尿病引起的威胁视力的损害。我们测试了两种具有不同作用机制的药物（醛糖还原酶抑制剂和中低浓度的阿司匹林），推理这两种药物共有的分子靶标将识别有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途径是最受糖尿病影响的单一功能途径，（iii）两种药物具有私人和共同的目标，其中TGF-β途径是两个共同的功能目标之一。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，并且根据记录糖尿病视网膜血管中 TGF-β 信号传导增加的其他结果，我们计划检验以下假设：过量的 TGF-β 信号传导有助于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型 TGF-β I 型受体激酶小分子抑制剂 SM16，它具有口服活性，是转化步骤中最有吸引力的特征。我们的目标是在糖尿病大鼠中开发并验证一种基于 SM16 的药物策略，用于非侵入性、长期、靶向预防视网膜血管中过多的 TGF-β 信号传导。确切的目标是使 TGF-β 信号转回到控制值而不降低基础 TGF-β 活性。我们将使用该抑制剂来了解过量 TGF-β 信号传导对糖尿病视网膜血管的分子影响。然后，我们将测试通过消除这些影响，视网膜毛细血管是否可以免受细胞死亡和重塑的影响，从而导致视网膜毛细血管最终死于糖尿病。在同一只大鼠中，我们还将检查 SM16 对典型肾脏病理发展的影响。最后，我们将检查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的积极结果相结合，将确定过量的 TGF-β 信号传导是糖尿病视网膜病变血管病理学的一个促成因素，并将刺激安全调节人类 TGF-β 活性的药物的研究和开发。此外，这些研究有望为抗 TGF-β 疗法应用于其他病理学提供范例。