Urokinase-type plasminogen activator and Alzheimer's

尿激酶型纤溶酶原激活剂与阿尔茨海默病

• 批准号: 6656286
• 负责人: Steven Estus
• 金额: $ 10.07万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6656286
• 关键词: Alzheimer's disease; amyloid proteins; clinical research; enzyme activity; enzyme mechanism; gene expression; genetic susceptibility; homozygote; human subject; human tissue; laboratory mouse; linkage disequilibriums; patient oriented research; plasminogen activator; postmortem; single nucleotide polymorphism; urokinase

DESCRIPTION (provided by applicant): Genetic factors that contribute to Alzheimer's disease (AD) susceptibility are critical to our understanding and early diagnosis of the disease. A chromosome 10 region contains at least one susceptibility locus for late onset Alzheimer's disease, and is associated with increased amyloid-B (ADi) plasma levels. The gene encoding urokinase-type plasminogen activator (uPA) is within this implicated region. UPA is induced by AB-treated neurons in vitro and in the Hsiao mouse model of AB burden in vivo. Moreover, uPA converts plasminogen to the active protease plasmin, which degrades both nonaggregated and aggregated AB with physiologic efficiency. In summation, ADi induces uPA, which can in turn lead to AB degradation, suggesting a self-regulated system for clearance of AB aggregates. Considering these data overall we hypothesize that the chromosome 10 loci includes a uPA polymorphism(s) that modulates uPA's ability to contribute to AD clearance. To evaluate this hypothesis, we propose to (i) identify uPA polymorphisms that segregate with Alzheimer's disease. In preliminary work we have identified two uPA polymorphisms that significantly segregate with AD susceptibility and are in strong linkage disequilibrium, including (i) a substitution of leu for pro at position 141 within uPA, which alters binding of the uPA zymogen to aggregated fibrin and (ii) a SNP two basepairs 3' to an AP-I site that is known to be critical for uPA induction. We also propose to (ii) Gain insight into the possible role of the at-risk uPA haplotype by comparing individuals homozygous for each genotype for relevant clinical and neuropathologic markers of Alzheimer's disease, (iii) Evaluate the effect of the uPA polymorphisms associated with AD risk on uPA expression and function, and (iv) Evaluate the role of uPA in AB clearance in vivo by quantifying AB accumulation in mice that are wildtype or genetically deficient for uPA. Overall, the focused approach proposed here will (i) directly evaluate the possible role of uPA polymorphisms as a risk factor(s) for Alzheimer's disease, and (ii) provide insights into possible mechanisms underlying differential uPA actions. These studies are significant in that the identification of additional genetic risk factors for Alzheimer's disease will aid in early AD diagnosis, and thereby facilitate drug discovery by identifying patients at high risk for AD prior to symptomology. Moreover, by evaluating possible mechanisms underlying the enhanced susceptibility to Alzheimer's disease, these studies may lead to the discovery of novel insights into the molecular mechanisms underlying Alzheimer's disease, and thereby suggest new therapeutic approaches.

描述（由申请人提供）：导致阿尔茨海默氏病（AD）易感性的遗传因素对于我们对疾病的理解和早期诊断至关重要。 10号染色体区域至少包含一个敏感性基因座，以供晚期阿尔茨海默氏病，并且与淀粉样蛋白-B（ADI）血浆水平升高有关。编码尿激酶型纤溶酶原活化剂（UPA）的基因在该含义区域内。 UPA在体外和体内AB负担的HSIAO小鼠模型中由AB处理的神经元诱导。此外，UPA将纤溶酶原转化为活性蛋白酶纤溶酶，该蛋白酶纤溶酶均以生理效率降解了非聚集和聚集的AB。总而言之，ADI诱导了UPA，这反过来又可能导致AB降解，这表明自我调节的系统可以清除AB聚集体。考虑到这些数据总体上，我们假设10个染色体10个基因座包括UPA多态性，该多态性调节了UPA有助于AD清除的能力。为了评估这一假设，我们建议（i）确定与阿尔茨海默氏病隔离的UPA多态性。 In preliminary work we have identified two uPA polymorphisms that significantly segregate with AD susceptibility and are in strong linkage disequilibrium, including (i) a substitution of leu for pro at position 141 within uPA, which alters binding of the uPA zymogen to aggregated fibrin and (ii) a SNP two basepairs 3' to an AP-I site that is known to be critical for uPA induction.我们还建议（ii）通过比较每个基因型纯合子的个体，以了解阿尔茨海默氏病的相关临床和神经病理学标志物（iii），通过比较每个基因型的纯合子，（iii）评估与UPA表达和功能相关的AD量相关的量化量相关的效果（IV）（IV）（iv）（iv），IV和功能率（IV）（iv）（iii iiv）（iii），（iii ii iii）将（III）评估（III）（IV）（IV）评估（IV）的效果（IV），则（iiii iii）通过（III）进行了（IV）的效果，以了解（ii）（ii）。在野生型或遗传上缺乏UPA的小鼠中积累。 总体而言，此处提出的重点方法将（i）直接评估UPA多态性作为阿尔茨海默氏病的危险因素的可能作用，并且（ii）对差异化行动的基本机制提供了见解。这些研究很重要，因为鉴定阿尔茨海默氏病的其他遗传危险因素将有助于早期AD诊断，从而通过识别症状前AD高风险的患者来促进药物发现。此外，通过评估增强对阿尔茨海默氏病易感性的可能机制，这些研究可能会导致发现对阿尔茨海默氏病的分子机制的新见解，从而提出新的治疗方法。