Retinal blood flow regulation in early diabetes

早期糖尿病的视网膜血流调节

基本信息

批准号：
8721962
负责人：
NORMAN R HARRIS
金额：
$ 35.28万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721962
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

项目摘要

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.

描述（由申请人提供）：糖尿病视网膜病变是美国劳动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 型糖尿病患者在接受糖尿病视网膜病变治疗后都会出现一定程度的视网膜病变。患糖尿病20年。由于缺乏可用的治疗方法，了解视网膜病变进展的重要性怎么强调都不为过，部分原因是我们对病理机制的了解不足。许多研究人员认为缺氧在糖尿病视网膜病变的进展中发挥着核心作用，有多种因素导致缺血和毛细血管闭塞。灌注损失被认为会导致氧气输送不足和随后产生血管生成因子，从而导致视网膜表面可渗透和出血的血管生长，从而干扰光传输。我们在拟议的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一个重要空白。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核心作用，因此很少有人关注过量氧气可能发挥的先行作用也就不足为奇了。我们假设糖尿病视网膜中发生的最初的过度氧合可能与早期耗氧量的减少有关，这至少可以部分解释为细胞死亡和视网膜变薄。随着消耗量的减少，正常的血液流入组织将为剩余细胞提供比所需更多的氧气。过量的氧气会引起自动调节血管收缩和血流量降低，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清除。旨在提高流速的处理可能会夸大现有的氧气过量，但不幸的是，会增加潜在有害的氧化剂的产生。因此，从转化的角度来看，有必要考虑血管舒张干预措施的优点和缺点，这将在以下具体目标中进行：（1）检验以下假设：旨在增强视网膜血流的干预措施会夸大过度氧合，从而导致视网膜血流量增加。存在于糖尿病视网膜早期，(2) 检验血管舒张干预措施引起的过度氧过多会增强糖尿病视网膜组织中氧化剂的产生这一假设，(3) 检验假设糖尿病视网膜中的血管舒张干预将受到血管收缩的自动调节途径的反对，血管收缩的自动调节途径将试图限制过度氧合，以及（4）检验糖尿病视网膜中的血管舒张干预将减轻毛细血管闭塞并改善神经功能的假设。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hypoxia and the expression of HIF-1alpha and HIF-2alpha in the retina of streptozotocin-injected mice and rats.

DOI：
10.1016/j.exer.2009.12.002
发表时间：
2010-03
期刊：
EXPERIMENTAL EYE RESEARCH
影响因子：
3.4
作者：
Wright, William S.;McElhatten, Robert M.;Messina, Jodine E.;Harris, Norman R.
通讯作者：
Harris, Norman R.

Expression of thromboxane synthase and the thromboxane-prostanoid receptor in the mouse and rat retina.

小鼠和大鼠视网膜中血栓素合酶和血栓素-前列腺素受体的表达。

DOI：
10.1016/j.exer.2009.05.008
发表时间：
2009
期刊：
Experimental eye research
影响因子：
3.4
作者：
Wright,WilliamS;McElhatten,RobertM;Harris,NormanR
通讯作者：
Harris,NormanR

Retinal blood flow abnormalities following six months of hyperglycemia in the Ins2(Akita) mouse.

DOI：
10.1016/j.exer.2012.03.003
发表时间：
2012-05
期刊：
EXPERIMENTAL EYE RESEARCH
影响因子：
3.4
作者：
Wright, William S.;Yadav, Amit Singh;McElhatten, Robert M.;Harris, Norman R.
通讯作者：
Harris, Norman R.

Attenuation of diabetes-induced retinal vasoconstriction by a thromboxane receptor antagonist.