Retinal blood flow regulation in early diabetes

描述（申请人提供）：糖尿病视网膜病变是美国工作年龄人群失明的主要原因，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，理解视网膜病变进展的重要性不能被夸大，这部分是由于我们对病理机制的认识不足。许多研究者认为缺氧在糖尿病视网膜病变的进展中起着重要作用，有几个因素导致缺血和毛细血管闭塞。灌注的损失被认为导致氧气输送不足和随后的血管生成因子的产生，从而导致视网膜表面上的渗透性和扩张性血管的生长，其干扰光透射。我们的主要假设进行测试，在拟议的工作是新颖的，填补了一个重要的空白，我们的理解糖尿病视网膜病变。我们计划探索潜在的悖论，即早期氧过剩导致糖尿病视网膜随后缺氧。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，因此很少有人关注过量氧气可能的作用也就不足为奇了。我们假设在糖尿病视网膜中发生的初始氧合过度可能与氧消耗的早期减少有关，这至少可以部分地解释为细胞死亡和视网膜变薄。随着这种消耗的减少，正常的血液流入组织将提供比剩余细胞所需更多的氧气。过量的氧气诱导自动调节性血管收缩和血流速度降低，这可能导致毛细血管阻塞和缺血，从而阻碍神经元功能、营养输送和代谢物清除。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，增加了潜在的有害氧化剂的产生。因此，从转化的角度来看，有必要考虑血管舒张干预的优点和缺点，如将在以下特定目标中进行的：（1）检验以下假设：针对增强视网膜血流的干预将夸大糖尿病视网膜中早期存在的过度氧合，（2）检验由血管舒张干预诱导的过度氧过量将增强糖尿病视网膜组织中氧化剂的产生的假设，（3）检验糖尿病视网膜中的血管舒张干预将被试图限制过度氧合的血管收缩的自动调节途径所对抗的假设，以及（4）检验糖尿病视网膜中血管舒张干预将减弱毛细血管阻塞并改善神经功能的假设。 公共卫生相关性：我国人口中有很大一部分患有糖尿病，其中大多数人会出现视力问题。糖尿病视网膜病变是美国成年人失明的主要原因，患有这种疾病的患者在预防视力下降方面的治疗选择有限。本申请中提出的工作针对疾病的早期阶段，在该时间点，我们发现过多的视网膜氧可能导致视网膜血液灌注的有害减少。

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. PUBLIC HEALTH RELEVANCE: A large proportion of our population has diabetes, and most of these individuals will develop vision problems. Diabetic retinopathy is the leading cause of blindness in US adults, and patients with this disease have limited treatment options to prevent the decline in vision. The work proposed in this application targets the early phase of the disease, a time point in which we have discovered that too much retinal oxygen might cause harmful decreases in retinal blood perfusion.