ROLES OF VASCULAR AMYLOID BETA PROTEIN PRECURSOR

拟议研究的目标有两个方面， PN的生物化学、功能特性和细胞生物学领域， 2/AbetaPP目前由两项研究赠款资助。 一是 PN-2/AbetaPP和凝血因子之间的生物化学相互作用将 追究具体而言，本建议将侧重于研究 关于凝血因子X1 a和PN-2/AbetaPP之间的相互作用 以及高分子量激肽原的作用和 生物表面的相互作用。 此外， 的蛋白酶抑制和潜在的抗凝特性， 相关AbetaPP的重组Kunitz型蛋白酶抑制剂结构域- 同源物计划，以更好地了解功能相关性 这种蛋白质与PN 2/AbetaPP同源。其次，在一个有点不同，但 相关和重要的一系列研究，PN-2/AbetaPP表达和 死后人脑组织中脑血管的处理 并在培养的脑血管平滑肌细胞中进行研究。 这些系列研究将开始阐明PN-2/AbetaPP 通常可以作为血管内的抗凝剂， 它可能异常地参与患者的脑内出血， 患有一种与阿尔茨海默病有关的罕见疾病， 遗传性脑出血伴淀粉样变性-Dutch型。更好 了解PN的生物化学和脑血管细胞生物学， 2/AbetaPP将提供对其正常功能以及 在某些疾病中这种蛋白质病理生物化学和病理生理学 states.

The objectives of the proposed studies are two-fold and reflect research areas in the biochemistry, functional properties, and cell biology of PN- 2/AbetaPP that are currently funded by two research grants. First, the biochemical interactions between PN-2/AbetaPP and coagulation factors will be investigated. Specifically, the present proposal will focus on studies concerning interactions between coagulation factor X1a and PN-2/AbetaPP and the effects of high molecular weight kininogen and the effects of biologic surfaces on these interactions. In addition, characterization of the protease inhibitory and potential anticoagulant properties of a recombinant Kunitz-type protease inhibitor domain of a related AbetaPP- homolog are planned to better understand the functional relatedness of this homolog protein to PN2/AbetaPP. Second, in a somewhat different, but related and important series of studies, PN-2/AbetaPP expression and processing in cerebral blood vessels from postmortem human brain tissue and in cultured cerebrovascular smooth muscle cells will be investigated. These series of investigations will begin to elucidate how PN-2/AbetaPP may normally serve as an anticoagulant in the cerebrovasculature and how it may abnormally be involved with intracerebral hemorrhaging in patients with a rare disorder that is related to Alzheimer's disease known as hereditary cerebral hemorrhage with amyloidosis-Dutch type. Better understanding of the biochemistry and cerebrovascular cell biology of PN- 2/AbetaPP will provide insight into its normal function as well as the patho-biochemistry and pathophysiology of this protein in certain disease states.