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

 描述(由申请人提供)：老年人的血管认知障碍(VCI)在美国是一个医疗危机。VCI与高血压密切相关。美国有6700万成年人(占总人口的33.3%)患有高血压，超过40%的高血压患者患有VCI。治疗高血压的医疗保险费用超过470亿美元/年，痴呆症的医疗保险费用超过1590亿美元/年。老年人，尤其是高血压伴血管认知障碍(VCI)发生率较高的人群，通常具有肌源性反应和脑血流量(CBF)自动调节功能受损。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，在脑循环中不能自我调节，这种损害可以通过替换包含ADD3等15个基因的棕色挪威(BN)大鼠1号染色体的2.4Mbp来修复。在前期研究中，我们发现ADD3在FHH大鼠中的表达较FHH.1BN大鼠降低，用DsiRNA敲除ADD3后，FHH.1BN大鼠大脑中动脉的血管反应性又恢复受损。使用我们新产生的ADD3转基因和基因敲除(KO)大鼠模型，我们在整个动物水平上也有初步结果支持这一观点。正如预期的那样，ADD3的KO损伤，野生型(WT)ADD3的敲击增强了体外新鲜分离的MCA的肌源性反应和体内CBF的自动调节。此外，我们还观察到血管重构、血脑屏障(BBB)渗漏、神经变性、学习和记忆认知障碍等都是FHH大鼠诱导高血压后VCI的特征。因此，我们推测ADD3在调节受损的肌源性反应和CBF自身调节中起重要作用，并在FHH大鼠年龄和高血压相关性VCI的发生发展中起重要作用。在这个方案中，我们将使用我们新创建的ADD3转基因FHH大鼠(FHH.Add3TG)和FHH大鼠来检测CBF的肌源性反应和自我调节，以及VCI随着年龄的增长和高血压诱导后的发展。这些研究将为ADD3在调节生肌反应中的作用及其在年龄相关性小血管疾病中的作用提供新的见解，特别是在高血压患者中，并为科学界提供第一个生肌反应受损的遗传动物模型，以研究VCI随年龄增长的机制。这一结果将对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。

 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.