STRUCTURAL ASPECTS OF ABPP FUNCTION AND PATHOLOGY

该实验室的长期目标是详细描述 阿尔茨海默病淀粉样β蛋白的结构和功能 前体(ABPP)。除了与阿尔茨海默氏症有牵连外，这 最近在血小板中发现了蛋白质，而这种蛋白质的突变版本 β-肽本身与遗传性脑出血有关， HCHWA-D。对…的功能(或功能失调)行为的描述 正常和病理状态下的ABPP可能会提示新的治疗方法 治疗神经退行性疾病的方法，如 Aizheimers以及中风等心血管疾病。 考虑到这些目标，我们提议的研究的主旨是 两个方面：a)进一步获得有关的高分辨率结构信息 ABPP，这可能产生对功能的洞察；以及b)使用结构 我们已经拥有的信息，试图识别大脑中的蛋白质 在与ABPP或其亚片段特异相互作用的血液中。 我们在资助金的任期内的具体目标是： 1.通过以下方式开始全面研究ABPP的结构和功能 进行N-末端结构域的高分辨率“丙氨酸扫描”。 2.大量生产纯化的重组ABPP N-末端 X射线结晶学和多维结构研究领域 核磁共振。 3.研究β-淀粉样蛋白纤维作为激动剂的可能作用。 人组织纤溶酶原激活剂。 4.分离结合同源蛋白酶或酯酶的分子克隆 到ABPP的库尼茨领域。 这项工作如果成功，应该会开始引起人们对 身体中的蛋白质，在大脑和血液中，相互作用 与ABPP合作。这一信息将有助于阐明ABPP在这两个方面所扮演的角色 在健康组织和患病组织中。

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.