Multidimensional interrogation of microvascular matrisome abnormalities in cerebral smallvessel diseases

大脑的重量仅为体重的2%，但消耗了通过血管输送到大脑的几乎四分之一的身体能量。在大脑缺乏血液供应的情况下，其自身的能量储备仅持续几分钟，因此脑血管的正常运作对大脑健康至关重要。众所周知，大脑中小血管的功能缺陷会导致中风和痴呆。事实上，全球四分之一的缺血性中风、绝大多数自发性脑内出血和约三分之一的痴呆病例是由影响这些小脑血管的疾病引起的，也称为脑小血管疾病（cSVD）。cSVD是一组异质性疾病，目前还不了解问题所在，因此这些疾病缺乏有效的治疗方法。构成血管壁的细胞嵌入在一个称为基质体的复杂蛋白质网中。改变的基质体蛋白水平可导致小血管病变，这是cSVD的基础。我们的假设是，小脑血管中的基质体变化在cSVD中占据中心地位。本项目旨在解决以下3个问题：1）是什么驱动了cSVD中的这些基质体变化？2)HTRA 1是一种基质体蛋白，在cSVD中起关键作用，其水平/活性的变化如何导致疾病表现和收缩性血管细胞的死亡，3）相反，一些基质体修饰是否具有保护作用，防止疾病表现的发生？总之，从我们的研究中获得的信息可以用来为未来的研究提供灵感，以开发治疗方法-直接干扰或纠正疾病途径或刺激现有的保护途径。

Brain weighs only 2% of the body weight but consumes almost one fourth of all body’s energy delivered into brain via blood vessels. In the case of a lack of blood supply into brain, its own energy reserve lasts only for couple of minutes and therefore a proper functioning of brain vessels is crucial for brain health. It is well known that defective functioning of small blood vessels in the brain causes stroke and dementia. In fact, one quarter of ischemic stroke, the vast majority of spontaneous intracerebral hemorrhage and about one third of dementia cases world-wide are caused by diseases affecting these small brain vessels, also called cerebral small vessel diseases (cSVDs). cSVD is an heterogeneous group of diseases and currently there is no understanding of what goes wrong and therefore these diseases lack an effective treatment. Cells that make up the vessel wall are embedded in a complex mesh of proteins called the matrisome. Altered levels of matrisome proteins can lead to small vessel lesions, the underpinning of cSVDs. Our hypothesis is that matrisome changes in small brain vessels take center stage in cSVDs. This project aims at addressing the 3 following questions: 1) What drive these matrisome changes in cSVDs? 2) How do changes in the levels/activity of HTRA1, a matrisome protein and key player in cSVDs, contribute to disease manifestations and death of contractile vascular cells and 3) conversely, can some matrisome modifications have a protective role, preventing the occurrence of disease manifestations? Altogether, the information obtained from our study can be used to get an inspiration for future studies to develop therapeutics – either directly to interfere or correct the disease pathway or to stimulate existing protective pathways.