Mechanisms of Amyloid Angiopathy-Related Hemorrhage

描述(申请人提供)：淀粉样血管病相关出血的机制淀粉样β-多肽(A-beta)在脑血管中的沉积(脑淀粉样血管病，CAA)是老年人的常见发现，在阿尔茨海默病患者中尤为明显。CAA最广为人知的并发症之一是原发性非创伤性脑出血；然而，CAA相关出血的分子发病机制尚不清楚。基质金属蛋白酶(MMPs)是一类降解细胞外基质(ECM)的蛋白，已被认为在全身血管重塑中发挥作用，尤其是明胶酶B，参与了多种血管病变。这一假说将得到验证，即在CAA中积聚在脑血管中的A-β诱导血管中的基质金属蛋白酶-9活性，并有助于自发性出血性中风的发生。特定目的1将验证A-β在体外刺激脑内皮细胞(CECs)和血管平滑肌细胞(SMCs)中的基质金属蛋白酶-9活性，促进细胞外基质降解的假设。具体目的2将探讨c-jun氨基末端激酶(JNK)信号通路及其随后激活的转录因子AP-1在AP诱导的CECs和SMC表达MMP9中的作用。具体目标3将检测淀粉样蛋白血管中的蛋白分解微环境，以确定它是否有利于脑淀粉样血管病变小鼠模型中基质金属蛋白酶-9的表达和活性。《特定目的4》将验证这样一种假说，即部分通过JNK/AP-1信号通路介导的脑血管中的基质金属蛋白酶-9活性增加，有助于老年APPsw小鼠自发性出血性中风的发生。这一建议中的实验应有助于加深对CAA相关出血的分子发病机制的理解，从而有助于未来预防自发性脑内出血的有效临床治疗方法的发展。

DESCRIPTION (provided by applicant): Mechanisms of Amyloid Angiopathy-Related Hemorrhage The deposition of amyloid-beta peptide (A-beta) in cerebral vessels (cerebral amyloid angiopathy, CAA) is a common finding in the elderly, and especially prominent in patients with Alzheimer's disease. One of the most widely recognized complications of CAA is primary nontraumatic intracerebral hemorrhage; however, the molecular pathogenesis of CAA-related hemorrhage is poorly understood. The matrix metalloproteinases (MMPs), a family of extracellular matrix (ECM)-degrading proteinases, have been postulated to play a role in systemic vascular remodeling, and MMP-9 (gelatinase B), in particular, has been implicated in a variety of vascular pathologies. The hypothesis will be tested that A-beta, which accumulates in cerebral blood vessels in CAA, induces vascular MMP-9 activity and contributes to the development of spontaneous hemorrhagic stroke. Specific Aim 1 will test the hypothesis that A-beta stimulates MMP-9 activity in cerebral endothelial cells (CECs) and vascular smooth muscle cells (SMCs) in vitro, enhancing ECM degradation. Specific Aim 2 will explore the role of the c-Jun N-terminal Kinase (JNK) signaling pathway and subsequent activation of the transcription factor, AP-1, in Ap-induced MMP-9 expression in CECs and SMCs in vitro. Specific Aim 3 will examine the proteolytic microenvironment in amyloid-laden vessels to determine if it favors MMP-9 expression and activity in a mouse model of cerebral amyloid angiopathy. Specific Aim 4 will test the hypothesis that increased MMP-9 activity in cerebral vessels, mediated in part by the JNK/AP-1 signaling pathway, contributes to the development of spontaneous hemorrhagic strokes in aged APPsw mice. Experiments in this proposal should lead to an enhanced understanding of the molecular pathogenesis of CAA-related hemorrhage, and thus aid the future development of effective clinical therapies for the prevention of spontaneous intracerebral hemorrhage.