The Role of Perlecan Domain V in Vascular Dementia

描述（由申请人提供）：尽管其发病率很高，但由于其病因多样，VaD的研究和理解仍然很不足。然而，VaD的这些多重原因的结果仍然是相同的——内皮细胞、星形胶质细胞、周细胞、神经元和细胞外基质（神经血管单元的组成部分）之间复杂耦合的破坏。我们假设细胞外基质在VaD的神经血管破坏中起关键作用。特别是，我们已经确定了一种突出的基质成分的生物活性片段，硫酸肝素蛋白多糖，perlecan，在实验性缺血性中风后调节内皮细胞功能中发挥重要作用。这个片段被称为域V (DV)，在中风的大脑中积极产生，似乎对大脑对损伤的反应很重要，因为它的缺失会导致更严重的中风损伤和更糟糕的结果。此外，卒中后DV卒中治疗可促进梗死周围新血液生长（血管生成）和神经修复的重要组成部分。由于细胞外基质重塑可能发生在导致VaD的血管病理中，我们假设DV是主动生成的，在调节脑内皮细胞功能中起关键作用，并且在分别对白质和灰质产生不同影响的BCAS和DB/AD两种VaD实验小鼠模型中给予DV可能改善内皮细胞功能和神经血管耦合。这将使我们能够确定白质和灰质内皮细胞功能障碍对VaD的影响以及DV对其的潜在影响。为了研究这些假设，我们提出了三个目标：目标1。测定BCAS和DB/AD小鼠模型中DV生成的程度和意义。目标2。测定DV在BCAS和DB/AD小鼠模型中的治疗潜力。目标3。确定VaD患者尸检脑组织中DV生成的程度和意义。这些研究的成功完成将增加我们对细胞外基质和血管生成在VaD中的作用的理解，并支持DV的治疗潜力。

DESCRIPTION (provided by applicant): Despite its prevalence, VaD remains woefully understudied and poorly understood, in part due to its diverse etiology. The outcome of these multiple causes of VaD, however, remains the same- disruption of the complex coupling between endothelial cells, astrocytes, pericytes, neurons, and the extracellular matrix, the components of the neurovascular unit. We hypothesize that the extracellular matrix plays a critical role in the neurovascular disruption of VaD. In particular, we have identified a biologicaly active fragment of one prominent matrix component, the heparan sulfate proteoglycan, perlecan, to play a major role in regulating endothelial cell function after experimental ischemic stroke. This fragment, termed domain V (DV), is actively generated in the stroked brain and appears to be important to the brain's response to injury inasmuch as its absence results in more significant stroke injury and worse outcome. Furthermore, DV stroke treatment after stroke enhances peri-infarct new blood growth (angiogenesis) and important component of neurorepair. As extracellular matrix remodeling is likely to occur in the vascular pathology leading to VaD, we hypothesize that DV is actively generated, plays a key role in regulating brain endothelial cell function, and may improve endothelial cell function and neurovascular coupling when administered in two experimental mouse models of VaD, the BCAS and the DB/AD models, which differentially impact white matter and gray matter, respectively. This will allow us to determine both the impact of white and gray matter endothelial cell dysfunction on VaD and DV's potential impact on it. To investigate these hypotheses, we propose three aims: Aim 1. Determine the extent and significance of DV generation in the BCAS and DB/AD mouse models. Aim 2. Determine the therapeutic potential of DV in the BCAS and DB/AD mouse models. Aim 3. Determine the extent and significance of DV generation in human autopsy brain from subjects with VaD. Successful completion of these studies will increase our understanding of the role of the extracellular matrix and angiogenesis in VaD, and support the therapeutic potential for DV.