Mechanisms of action of drugs that prevent experimental diabetic retinopathy

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途径是主要受糖尿病影响的单一功能途径，（iii）这两种药物有私人和共同的靶点，TGF-β途径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信号传导增加的其他结果，我们计划检验过度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SM 16，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SM 16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。确切的目标是在不降低基础TGF-β活性的情况下使TGF-β信号传导恢复到控制值。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鉴定过量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，并且将刺激药物的研究和开发以安全地调节人类中的TGF-β活性。此外，这些研究准备产生一个应用抗TGF-β治疗其他病理学的范例。

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.