Retinal blood flow regulation in early diabetes

描述（由申请人提供）：糖尿病视网膜病变是美国工作年龄人口失明的主要原因，几乎所有1型糖尿病患者和超过60%的2型糖尿病患者在患糖尿病20年后都有一定程度的视网膜病变。由于缺乏可用的治疗方法，了解视网膜病变进展的重要性不能被夸大，这在一定程度上是我们对病理机制知识不足的结果。许多研究者认为缺氧在糖尿病视网膜病变的进展中起着核心作用，有几个因素导致了缺血和毛细血管闭塞。灌注丧失被认为会导致氧气输送不足和随后血管生成因子的产生，从而导致视网膜表面可渗透和出血血管的生长，从而干扰光的透射。我们在这项工作中要测试的主要假设是新颖的，填补了我们对糖尿病视网膜病变理解的重要空白。我们计划探索潜在的悖论，即早期过量的氧气导致随后的缺氧在糖尿病视网膜。由于许多研究人员认为缺氧在糖尿病视网膜病变中起着核心作用，因此很少有人注意到过量氧气可能在糖尿病视网膜病变中起的作用。我们假设在糖尿病视网膜中发生的初始高氧合可能与早期耗氧量减少有关，这至少可以部分解释为细胞死亡和视网膜变薄。随着消耗的减少，正常的血液流入组织将提供比剩余细胞所需的更多的氧气。过量的氧气会引起血管收缩和血流速率降低，这可能导致毛细血管闭塞和缺血，从而阻碍神经元功能、营养物质输送和代谢物的去除。旨在提高流速的处理可能会夸大现有的氧气过剩，但不幸的是，增加了潜在有害的氧化剂的产生。因此，从翻译的角度来看，有必要考虑血管舒张干预的优点和缺点，具体目的如下：(1)验证旨在增强视网膜血流量的干预措施会加剧糖尿病视网膜早期存在的高氧合的假设；(2)验证由血管扩张干预引起的过度氧合会增强糖尿病视网膜组织中氧化剂产生的假设；(3)验证糖尿病视网膜的血管扩张干预将被试图限制高氧的血管收缩的自我调节途径所反对的假设；(4)验证糖尿病视网膜的血管扩张干预将减轻毛细血管闭塞并改善神经功能的假设。

DESCRIPTION (provided by applicant): Diabetic retinopathy is the leading cause of blindness in the working-age population of the United States, and nearly everyone with type-1diabetes and more than 60% with type-2 diabetes have some level of retinopathy after being diabetic for 20 years. The importance of understanding the progression of retinopathy cannot be overstated due to the lack of available treatments, which in part is a consequence of a deficiency in our knowledge of the pathological mechanisms. Many investigators suggest a central role for hypoxia in the progression of diabetic retinopathy, with several factors contributing to ischemia and capillary occlusion. The loss of perfusion is thought to lead to insufficient oxygen delivery and subsequent production of angiogenic factors, with consequential growth of permeable and hemorrhaging vessels on the surface of the retina that interferes with light transmission. Our primary hypothesis to be tested in the proposed work is novel and fills an important void in our understanding of diabetic retinopathy. We plan to explore the potential paradox that an early excess of oxygen leads to a subsequent deficiency of oxygen in the diabetic retina. Due to the central role in diabetic retinopathy that many researchers assign to hypoxia, it is not surprising that little attention has been given to the possible preceding role for excess oxygen. The initial hyperoxygenation that we hypothesize to occur in the diabetic retina could be related to the early decrease in oxygen consumption, which may be explained at least in part to the cell death and thinning of the retina. With this decrease in consumption, a normal flow of blood into the tissue would provide more oxygen than necessary to the remaining cells. An excess of oxygen induces autoregulatory vasoconstriction and a reduction in blood flow rate, which could contribute to capillary occlusion and ischemia that hampers neuronal function, nutrient delivery, and metabolite removal. Treatments designed to improve flow rates may exaggerate the existing oxygen excess, but unfortunately, increase the potentially harmful production of oxidants. Therefore, from a translational standpoint, it is necessary to consider both advantages and also disadvantages of vasodilatory interventions, as will be performed in the following specific aims: (1) Test the hypothesis that interventions directed toward enhancing retinal blood flow will exaggerate the hyperoxygenation that is present early in the diabetic retina, (2) Test the hypothesis that the exaggerated oxygen excess induced by vasodilatory interventions will enhance the production of oxidants in diabetic retinal tissue, (3) Test the hypothesis that vasodilatory interventions in the diabetic retina will be opposed by autoregulatory pathways of vasoconstriction that will attempt to limit hyperoxygenation, and (4) Test the hypothesis that vasodilatory interventions in the diabetic retina will attenuate capillary occlusion and improve neural function.