The Role of Perlecan Domain V in Vascular Dementia

描述（由申请人提供）：尽管其患病率，VaD仍然令人遗憾地研究不足和了解甚少，部分原因是其病因多样。然而，VaD的这些多种原因的结果仍然相同-内皮细胞、星形胶质细胞、周细胞、神经元和细胞外基质（神经血管单元的组分）之间的复杂耦合的破坏。我们假设细胞外基质在VaD的神经血管破坏中起着关键作用。特别是，我们已经确定了一个突出的基质成分，硫酸乙酰肝素蛋白聚糖，串珠素，发挥重要作用，在实验性缺血性中风后调节内皮细胞功能的生物活性片段。该片段，称为结构域V（DV），在中风脑中活跃地产生，并且似乎对脑对损伤的反应是重要的，因为其缺失导致更显著的中风损伤和更差的结果。此外，中风后DV中风治疗增强了梗死周围的新血液生长（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血管病理导致VaD，我们假设DV是积极产生的，在调节脑内皮细胞功能中起着关键作用，并可能改善内皮细胞功能和神经血管耦合时，在两个实验小鼠模型VaD，BCAS和DB/AD模型，其差异影响白色物质和灰质，分别。这将使我们能够确定白色和灰质内皮细胞功能障碍对VaD和DV的潜在影响的影响。为了研究这些假设，我们提出了三个目标：目标1。确定BCAS和DB/AD小鼠模型中DV生成的程度和意义。目标2.确定DV在BCAS和DB/AD小鼠模型中的治疗潜力。目标3：确定VaD受试者尸检脑中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.