STRUCTURAL ASPECTS OF ABPP FUNCTION AND PATHOLOGY

实验室的长期目标是详细描述 阿尔茨海默氏症β淀粉样蛋白的结构和功能 前体（ABPP）。 除了与老年痴呆症有关外， 最近在血小板中发现了一种蛋白质， β肽本身与遗传性脑出血有关， HCHWA-D。 对功能性（或功能障碍性）行为的描述 正常和病理状态下的ABPP可能提示新的治疗方法 治疗神经变性疾病的方法， 以及心血管疾病如中风。 考虑到这些目标，我们建议的研究重点是 二：a）进一步获得高分辨率结构信息， ABPP，这可能会产生对功能的见解;和B）使用结构 这些信息是我们用来识别大脑中的蛋白质的 和血液中与ABPP或其亚片段特异性相互作用的抗体。 我们在赠款期限内的具体目标是： 1. 为了开始对ABPP的结构和功能进行全面研究， 进行N-末端结构域的高分辨率“丙氨酸扫描”。 2. 生产大量纯化的重组ABPP N-末端 X射线晶体学和多维结构研究领域 匪r 3. 为了研究β淀粉样纤维作为刺激因子的可能作用， 人组织纤溶酶原激活剂。 4. 为了分离结合的同源蛋白酶或酯酶的分子克隆， 到ABPP Kunitz域。 这项工作如果取得成功，将开始使人们关注 大脑和血液中的蛋白质 关于ABPP 这一信息将有助于阐明ABPP扮演的角色， 在健康和病变组织中。

The long-term objective of the laboratory is a detailed characterization of the structure and the function of the Alzheimer's amyloid beta protein precursor (ABPP). Besides being implicated in Alzheimer's disease, this protein has recently been found in platelets, and a mutant version of the beta peptide itself has been linked to a hereditary cerebral hemorrhage, HCHWA-D. A description of the functional (or dysfunctional) behavior of ABPP in normal and pathological states might suggest new therapeutic approaches to the treatment of neurodegenerative diseases such as Aizheimers as well as cardiovascular disorders such as stroke. With these objectives in mind, the thrust of our proposed research is two-fold: a) to derive further high-resolution structural information about ABPP which might yield insights into function; and b) use the structural information that we already have to try to identify proteins in the brain and in the blood that specifically interact with ABPP or its subfragments. Our specific aims for the term of the grant are: 1. To begin a comprehensive study of the structure and function of ABPP by conducting a high resolution "alanine scan" of the N-terminal domain. 2. To produce large quantities of purified, recombinant ABPP N-terminal domain for structural studies by X-ray crystallography and multidimensional NMR. 3. To study the possible role of beta amyloid fibrils as stimulators of human tissue plasminogen activator. 4. To isolate molecular clones of cognate proteases or esterases that bind to the ABPP Kunitz domain. This work, if successful, should start to bring into focus the network of proteins in the body, both in the brain and in the blood, that interact with ABPP. This information will help elucidate the role ABPP plays both in healthy and in diseased tissue.