Retinal blood flow regulation in early diabetes

早期糖尿病的视网膜血流调节

• 批准号: 8182567
• 负责人: NORMAN R HARRIS
• 金额: $ 36万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8182567
• 关键词: Adult; Adverse effects; Affect; Age; Angiogenic Factor; Animals; Attention; Attenuated; Blindness; Blood capillaries; Blood flow; Brain Hypoxia-Ischemia; Cell Death; Cells; Consumption; Development; Diabetes Mellitus; Diabetic Retinopathy; Disadvantaged; Disease; Event; Excision; Growth; Hemorrhage; Hyperbaric Oxygenation; Hypoxia; Individual; Insulin-Dependent Diabetes Mellitus; Intervention; Ischemia; Knowledge; Lead; Neurons; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Oxidants; Oxygen; Oxygen Consumption; Pathway interactions; Patients; Perfusion; Phase; Population; Production; Reactive Oxygen Species; Regulation; Research Personnel; Retina; Retinal; Retinal Diseases; Risk; Rodent Model; Role; Surface; Testing; Time; Tissues; United States; Vision; Visual; Work; angiogenesis; blood glucose regulation; blood perfusion; capillary; diabetic; improved; improved functioning; laser photocoagulation; light transmission; novel; prevent; retina blood vessel structure; sound; therapy design; vasoconstriction

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.

描述（由申请人提供）：糖尿病性视网膜病是美国工作年龄人群失明的主要原因，几乎每个患有1型糖尿病类型的人和60％以上患有2型糖尿病的人都有一定程度的视网膜病变，糖尿病患者已有20年了。由于缺乏可用的治疗，理解视网膜病的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了解不足。许多研究者认为缺氧在糖尿病性视网膜病的进展中起着核心作用，其中有几个因素导致缺血和毛细血管阻塞。灌注的丧失被认为会导致氧递送不足和随后产生血管生成因子，并且在视网膜表面可渗透和出血血管的结果呈良性生长，从而干扰了光传输。我们在拟议的工作中要检验的主要假设是新颖的，并且在我们对糖尿病性视网膜病的理解中填补了重要的空白。我们计划探索潜在的悖论，即早期过量的氧气会导致随后的糖尿病视网膜氧气不足。由于许多研究人员将其分配给缺氧的糖尿病性视网膜病中核心作用，因此很少有人注意过多氧的可能作用。我们假设发生在糖尿病性视网膜中的最初的高氧化可能与氧气消耗的早期降低有关，这至少部分与视网膜的细胞死亡和稀疏有关。随着消耗量的减少，血液流入组织的正常流量将提供比其余细胞所需的更多的氧气。过量的氧气会诱导自动调节性血管收缩和血流量降低，这可能导致毛细血管阻塞和缺血，从而阻碍神经元功能，营养递送和代谢物去除。旨在提高流量的处理可能会夸大现有的氧气过量，但不幸的是，增加了潜在的有害氧化剂产生。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，这将在以下具体目的中进行，这将进行：（1）测试以下假设：针对增强视网膜血流的干预措施将依靠糖尿病的高度氧化，这是在糖尿病上的早期氧化的（2）脱氧于糖尿病上的氧化度（2）（2）（2）脱氧于糖尿病上（2）（2）（2）（2） （3）测试假说，糖尿病视网膜中血管降解性干预的假设将与血管收缩的自动调节途径相反，该途径将试图限制过度氧气，并且（4）（4）测试糖尿病性的糖尿病性糖尿病的假设会改善糖尿病性粘膜和糖尿病。 公共卫生相关性：我们很大一部分人群患有糖尿病，其中大多数人会出现视力问题。糖尿病性视网膜病是美国成年人失明的主要原因，患有这种疾病的患者的治疗选择有限，可以防止视力下降。该应用中提出的工作针对疾病的早期阶段，我们发现过多的视网膜氧气可能导致视网膜血液灌注有害下降。