Hypoxia-inducible Transcription Factor 1 (HIF-1) in Vascular Aging

缺氧诱导转录因子 1 (HIF-1) 与血管老化

基本信息

批准号：
7547648
负责人：
FARZANEH A SOROND
金额：
$ 10.77万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7547648
关键词：
Acute Age Aging Aging-Related Process Animals Blood Circulation Blood Flow Velocity Blood Vessels Blood flow Brain Hypoxia-Ischemia Brain region Carbon Dioxide Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Chelating Agents Chronic Clinical Trials Cocoa Powder Cognitive Complement Condition Congestive Heart Failure Consumption Coupling Data Deferoxamine Dementia Diabetic Angiopathies Dietary intake Disease Doppler Ultrasound Double-Blind Method Elderly Endothelium Erythropoietin Failure Flavonols Functional disorder Gene Targeting Genes Glucose Health Hour Human Hypoxia Impaired cognition In Vitro Infusion procedures Ingestion Injury Intake Iron Ischemia Knowledge Laboratories Lactate Dehydrogenase Lactate Dehydrogenases Link Measurement Measures Mediating Memory Mus Nitric Oxide Synthase Numbers Orthostatic Hypotension Oxygen Participant Peripheral Peripheral Blood Mononuclear Cell Placebos Play Procedures Process Proteins Quercetin Research Design Research Personnel Risk Factors Role Serum Stress Stroke Structure of posterior cerebral artery Syndrome System Testing Tissues Transcriptional Activation Vascular Diseases Vascular Endothelial Growth Factors Vascular remodeling Vasodilation Vasomotor Work age related aged aging population attenuation cerebral artery cerebrovascular cobaltous chloride cognitive function design drinking executive function functional disability healthy volunteer hypoxia inducible factor 1 improved middle cerebral artery neuropsychological placebo controlled study prevent programs response stem therapeutic target transcription factor volunteer

项目摘要

DESCRIPTION (provided by applicant): Advancing age is associated with a number of geriatric syndromes linked to hypoxic-ischemic injury, such as cerebral microvascular disease, autonomic failure with orthostatic hypotension, stroke, dementia and congestive heart failure. Underlying all of these conditions lies the aging blood vessel, damaged with a dysfunctional endothelium. Potential corrective therapies are unknown. Studies suggest that reduced activation of hypoxia inducible transcription factor-1 (HIF-1) may be involved in age-related vascular dysfunction. HIF-1 is a heterodimeric transcription factor expressed in all tissues in response to hypoxia and ischemia and activates a repertoire of target genes which function to protect oxygen or glucose deprived cells by activating a cassette of cellular, local and systemic responses. In animal studies, pharmacologic augmentation of HIF-1 can reverse age-related decline in HIF-1 activation. However, there have been no prior studies of HIF-1 activation in human aging. There are now two HIF-1 activators available for use in humans-the iron chelator Desferrioxamine (DFO) and a dietary flavonol, quercetin, which can be used to test the effects of acute and chronic HIF-1 activation on the vascular aging process. We have preliminary data to show that the infusion of DFO and the dietary intake of a flavonol-enriched cocoa drink are both associated with a significant cerebral vasodilation and increased cerebral blood flow response in elderly volunteers, as measured by transcranial Doppler ultrasound (TCD). The current proposal will examine the hypothesis that that HIF-1 can be pharmacologically activated in elderly humans and that pharmacologic augmentation of HIF-1 expression can improve age-related changes in cerebrovascular function. Specifically, using a double blind placebo controlled study design, we will compare DFO and quercetin mediated HIF-1 transcriptional activation and cerebrovascular responses in young and elderly healthy volunteers. DFO- and quercetin- mediated HIF-1 activation allows us to examine HIF-1 activation in aging as well as vascular responses to acute and chronic HIF-1 activation in cerebrovascular aging, which have not been previously investigated in humans. The TCD procedures routinely used in our laboratory allow us to assess these hypotheses as they relate to the cerebral arteries of humans, a field in which our knowledge is most deficient. Findings from our study will pave the way for clinical trials of HIF-1 activators in a number of hypoxic-ischemic geritaric disorders, especially cerebrovascular disorders such as ischemia and vascular cognitive impairment, which pose a significant health burden in our aging population.

描述（由申请人提供）：前进的年龄与与缺氧 - 缺血性损伤有关的许多老年综合症有关，例如脑微血管疾病，具有体位性低血压，中风，痴呆症和充血性心力衰竭的自主神经衰竭。所有这些疾病的基础是衰老的血管，患有功能失调的内皮受损。潜在的纠正疗法未知。研究表明，低氧诱导转录因子1（HIF-1）的激活可能涉及与年龄相关的血管功能障碍。 HIF-1是一种异二聚体转录因子，该因子在所有组织中响应低氧和缺血，并激活靶基因的曲目，该曲目通过激活细胞，局部和全身反应的盒子来保护氧或葡萄糖剥夺细胞。在动物研究中，HIF-1的药理学增强可以逆转与年龄相关的HIF-1激活下降。但是，没有先前研究人类衰老中的HIF-1激活。现在有两个HIF-1激活剂可用于人类 - 铁螯合剂Desferrioxamine（DFO）和饮食中黄酮醇槲皮素，可用于测试急性和慢性HIF-1激活对血管老化过程的影响。我们拥有初步数据，以表明DFO的输注和富含黄酮醇的可可饮料的饮食摄入均与老年人志愿者的大脑血管舒张作用和大脑血流反应增加有关，如经颅多普勒超声（TCD）所测量。当前的建议将研究以下假设：HIF-1可以在老年人中被药理激活，而HIF-1表达的药理学增强可以改善与年龄相关的脑血管功能变化。具体而言，使用双盲安慰剂对照研究设计，我们将比较年轻和老年人健康志愿者的DFO和槲皮素介导的HIF-1转录激活和脑血管反应。 DFO和槲皮素介导的HIF-1激活使我们能够检查衰老中的HIF-1激活，以及对脑血管衰老急性和慢性HIF-1激活的血管反应，这些反应以前尚未在人类中进行过研究。在我们的实验室中通常使用的TCD程序使我们能够评估这些假设，因为它们与人类的大脑动脉相关，这是我们知识最不足的领域。我们研究的发现将为HIF-1激活剂的临床试验铺平道路，以多种缺氧 - 缺血性的老年疾病，尤其是脑血管疾病，例如缺血和血管认知障碍，这在我们老化的人群中造成了重大健康负担。