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Animal model of impaired autoregulation for study of age related vascular cognitive impairment

用于研究年龄相关血管认知障碍的自动调节受损动物模型

基本信息

批准号：
9197938
负责人：
Fan Fan
金额：
$ 22.88万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9197938
关键词：
Adult Age Age of Onset Aging Alzheimer&apos s Disease Animal Genetics Animal Model Animals Back Blood - brain barrier anatomy Blood Vessels Brain Cerebral perfusion pressure Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Chromosomes, Human, Pair 1 Chronic Chronic Kidney Failure Communities Dementia Development Edema Elderly Exhibits Extravasation Gene Family Genes Genetic Genetic Predisposition to Disease Homeostasis Human Genome Hypertension Impaired cognition Impairment In Vitro Incidence Individual Injury Knock-in Knock-out Laboratories Learning Link Mediating Medical Medicare Memory Microcirculation Microvascular Dysfunction Modeling Mutation Names Nerve Degeneration Norway Organ Oxygen Patients Play Population Rattus Rattus norvegicus Regulation Reporting Role Single Nucleotide Polymorphism Stroke Testing Transgenic Organisms Treatment Cost United States Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Vascular remodeling adducin age related aged base cerebrovascular cognitive ability diabetic patient gamma-adducin genome wide association study hypertension treatment in vivo insight knock-down middle cerebral artery normotensive novel pressure prevent protein function public health relevance response transmission process

项目摘要

DESCRIPTION (provided by applicant): Vascular cognitive impairment (VCI) in elderly is a medical crisis in the United States. VCI is closely associated with hypertension. 67 millions of adults in the United States (33.3% of the population) have hypertension and over 40% of hypertensive patients develop VCI. The Medicare costs for the treatment of hypertension exceeds $47 billion/year and 159 billion/year for dementia. Aged people, especially those with hypertension that is associated with a higher incidence of developing vascular cognitive impairments (VCI) commonly have impaired myogenic response and autoregulation of cerebral blood flow (CBF). However, the mechanism of how these cerebral vascular impairments contribute to the development of VCI is still obscure, part of the reason has been the lack of genetic animal models exhibiting an impaired myogenic response. We first discovered that FHH rats have impaired myogenic response of middle cerebral artery (MCA) and fail to autoregulate in the cerebral circulation, and this impairment is restored by substitution of 2.4 Mbp of chromosome 1 of Brown Norway (BN) rats containing 15 genes including Add3. In the preliminary studies, we found that the expression of Add3 is reduced in FHH relative to FHH.1BN rats and the rescued vascular reactivity of MCA in FHH.1BN rats was back to be impaired after knocking down of Add3 using DsiRNA. We also have preliminary results in the whole animal level to support this view using our newly generated Add3 transgenic and knockout (KO) rat models. As expected, KO of Add3 impairs, and knockin of wildtype (WT) Add3 enhances the myogenic response in freshly isolated MCA in vitro and autoregulation of CBF in vivo. Moreover, we observed vascular remodeling, blood-brain barrier (BBB) leakage, neurodegeneration, learning and memory cognitive impairments those are all characters' of VCI after induction of hypertension in FHH rats. Thus, we hypothesize that Add3 plays an important role in the regulation of impaired myogenic response and autoregulation of CBF, and contributes to the development of age and hypertension related VCI in FHH rats. In this proposal, we will use our newly created Add3 transgenic FHH rats (FHH.Add3TG) vs. FHH rats to examine the myogenic response and autoregulation of CBF, as well as the development of VCI as they age and after the induction of hypertension. These studies should provide novel insights into the role of Add3 in the regulation of the myogenic response and its contribution to age-related small vessel disease, especially in hypertensive individuals, and supply the scientific community with the first genetic animal model in which the myogenic response is impaired to study mechanisms involved in VCI as age. The results will be critical for the development of new treatments to postpone the onset of age and hypertension related vascular diseases.

描述（由申请人提供）：老年人血管性认知障碍（VCI）在美国是一种医疗危机。VCI与高血压密切相关。美国有6700万成年人（占人口的33.3%）患有高血压，超过40%的高血压患者发生VCI。治疗高血压的医疗保险费用超过470亿美元/年，治疗痴呆症的费用超过1590亿美元/年。老年人，特别是那些与血管性认知障碍（VCI）发生率较高相关的高血压患者，通常具有受损的肌源性反应和脑血流量（CBF）的自动调节。然而，这些脑血管损伤如何促进VCI发展的机制仍然不清楚，部分原因是缺乏表现出肌源性反应受损的遗传动物模型。我们首次发现FHH大鼠大脑中动脉（MCA）的肌源性反应受损，并且不能在脑循环中进行自动调节，并且通过替换包含Add 3等15个基因的Brown Norway（BN）大鼠1号染色体的2.4 Mbp来恢复这种损伤。在初步研究中，我们发现相对于FHH. 1BN大鼠，FHH. 1BN大鼠中Add 3的表达减少，并且在使用DsiRNA敲低Add 3后，FHH. 1BN大鼠中MCA的挽救的血管反应性恢复受损。我们也有初步的结果，在整个动物水平，以支持这一观点，使用我们新产生的Add 3转基因和敲除（KO）大鼠模型。正如预期的那样，KO的Add 3损害，和敲入野生型（WT）的Add 3增强肌原性反应，在新鲜分离的MCA在体外和CBF在体内的自动调节。此外，我们还观察到FHH大鼠高血压后血管重构、血脑屏障（blood-brain barrier，BBB）渗漏、神经退行性变、学习记忆和认知功能障碍等均为VCI的特征。因此，我们推测，Add 3在调节受损的生肌反应和CBF的自动调节中起着重要作用，并有助于FHH大鼠中年龄和高血压相关VCI的发展。在这项提议中，我们将使用我们新创建的Add 3转基因FHH大鼠（FHH.Add3TG）与FHH大鼠来检查CBF的生肌反应和自动调节，以及随着年龄的增长和诱导高血压后VCI的发展。这些研究应提供新的见解Add 3在调节肌源性反应的作用及其对年龄相关性小血管疾病的贡献，特别是在高血压个体中，并为科学界提供第一个遗传动物模型，其中肌源性反应受损，以研究年龄相关的VCI机制。这些结果对于开发新的治疗方法以推迟年龄和高血压相关血管疾病的发病至关重要。