Mechanisms of action of drugs that prevent experimental diabetic retinopathy

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。 通过逐步更广泛地实施强化降糖措施，预防变得触手可及 控制，我们预计添加的药物是有效的预先排空组织的影响 残留的高血糖和安全的长期服用将使预防成为现实。没有 临床上可使用的辅助药物，并且没有关于药物类型的严格的正面或负面信息 这可能在预防人类糖尿病视网膜病变方面有效。因此，我们试图从毒品中学习 预防实验性糖尿病视网膜病变，分子过程必须在视网膜血管中沉默 以防止糖尿病对视力造成的损害。我们测试了两种不同的药物 作用机制(一种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点将确定候选致病途径 进一步调查。实验表明，在大鼠中，(I)糖尿病改变了多个基因的表达 视网膜血管中的基因，(Ii)转化生长因子-β途径是受糖尿病影响最大的单一功能途径， 和(3)这两种药物既有共同的靶点，也有单独的靶点，转化生长因子途径是两个靶点之一 共同的功能目标。鉴于转化生长因子途径的过度活跃可以解释大部分血管 糖尿病视网膜病变的组织病理学，以及记录转化生长因子-β信号增加的其他结果 在糖尿病视网膜血管中，我们计划测试过度的转化生长因子-β信号有助于 糖尿病视网膜病变的特征性血管病变。这个项目特别令人兴奋，因为 口服一种名为SM16的新型I型转化生长因子受体激酶小分子抑制剂的机会 Active，这是翻译步骤最吸引人的功能。我们的目标是在糖尿病大鼠身上开发和验证一种药物 基于SM16的非侵入性、长期和靶向预防血管内皮细胞过度转化生长因子β信号转导的策略 视网膜血管。准确的目标是在不降低基础转化生长因子-β的情况下，使转化生长因子-β信号恢复到控制值。 ？活动。我们将使用该抑制剂来了解过度的转化生长因子-β信号在糖尿病视网膜中的分子作用 船只。然后，我们将测试通过去除这些影响，视网膜毛细血管是否受到保护 细胞死亡和重塑导致它们最终死于糖尿病。在同一只大鼠身上，我们还将检查 SM16在典型肾脏病理发生发展中的作用最后，我们将研究转化生长因子？ 人糖尿病视网膜血管(死后眼)的通路。一系列积极结果的结合 临床前研究和人类糖尿病视网膜将确定过度的转化生长因子-β信号是导致 糖尿病视网膜病变的血管病理并将刺激药物的研究和开发 安全地调节人类体内的转化生长因子-β活性。此外，这些研究准备产生一个范例，以 抗转化生长因子治疗在其他病理中的应用。

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.