Role of the tPA/plasmin System in Alzheimers Disease

tPA/纤溶酶系统在阿尔茨海默病中的作用

• 批准号: 7112914
• 负责人: SIDNEY STRICKLAND
• 金额: $ 38.16万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-25 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112914
• 关键词: Alzheimer' s disease; amyloid proteins; disease /disorder model; fibrin; genetically modified animals; laboratory mouse; neuropharmacology; pathologic process; plasmin; plasminogen activator; plasminogen activator inhibitors

DESCRIPTION (provided by applicant): The overall hypothesis of this proposal is that the tissue plasminogen activator/plasminogen (tPA/plg) fibrinolytic cascade, a proteolytic system which has been implicated in the clearance of amyloid-beta (A-beta) peptide, is an important pathway to investigate for developing possible therapeutic agents against Alzheimer's disease (AD). The abnormal deposition of A-beta in the parenchyma and blood vessels of the brain is a pathological hallmark of AD, the most common cause of dementia and cognitive decline in the aged. Additionally, epidemiological studies indicate that diseases that compromise the circulatory system are risk factors for the development of AD, and imply that AD has a cerebrovascular component. The objectives of this proposal are to investigate the role of the tPA/plg system in the progression of AD-like pathology in transgenic mice overexpressing the amyloid-beta precursor protein (A-betaPP). The tPA/plg system activity is depressed in AD transgenic mice and in individuals with AD, due to the expression of plasminogen activator inhibitor-1 (PAl-l), a protein overexpressed during inflammation, commonly seen in AD. To accomplish this goal, we propose three specific aims. First, we plan to investigate the effects of the loss of tPA, plg, or PAl-1 expression in A-betaPP transgenic mice in a C57/BI6 background. Second, we plan to investigate the role of fibrin deposition in exacerbating the pathology and cerebrovascular dysfunction in AD. Third, we plan to identify new compounds that block the interaction of PAl-1 and tPA, and to test these, along with known PAl-1 inhibitors, for their effects in AD mouse models. These experiments will take advantage of transgenic and knockout mouse lines as in vivo paradigms for the development of possible therapeutic intervention strategies, targeting the tPA/plasmin cascade, against AD progression

描述（由申请人提供）：该建议的总体假设是组织纤溶酶原激活剂/纤溶酶原（TPA/PLG）纤维蛋白溶解级联反应，这是一种蛋白水解系统，该系统与清除淀粉样β（A-Beta）肽的清除有关，是针对ALEASETERS的重要途径，以调查ADEAPETICETERSETERASETERASETERAIMEIMEIMEIMEIMEIMEIMETETETETETETE。 A-beta在实质中的异常沉积和大脑的血管是AD的病理标志，这是老年痴呆症和认知能力下降的最常见原因。此外，流行病学研究表明，损害循环系统的疾病是AD发展的危险因素，这意味着AD具有脑血管成分。该提案的目标是研究TPA/PLG系统在过表达淀粉样蛋白β前体蛋白（A-BetApp）的转基因小鼠中AD样病理学进展中的作用。由于纤溶酶原激活剂抑制剂-1（PAL-L）的表达，TPA/PLG系统的活性在AD转基因小鼠和AD个体中抑郁，这种蛋白质在炎症过程中过表达，通常在AD中看到。为了实现这一目标，我们提出了三个具体目标。首先，我们计划研究C57/BI6背景中A-BetApp转基因小鼠TPA，PLG或PAL-1表达丢失的影响。其次，我们计划研究纤维蛋白沉积在加剧AD中病理学和脑血管功能障碍中的作用。第三，我们计划鉴定阻断PAL-1和TPA相互作用的新化合物，并与已知的PAL-1抑制剂一起测试它们在AD小鼠模型中的影响。这些实验将利用转基因和基因敲除小鼠系作为体内范式，以开发可能的治疗干预策略，靶向TPA/plasmin级联反应AD的进展